ClinVar Genomic variation as it relates to human health
NM_000342.4(SLC4A1):c.286C>T (p.Arg96Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(2); Benign(1); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000342.4(SLC4A1):c.286C>T (p.Arg96Cys)
Variation ID: 323517 Accession: VCV000323517.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 44260698 (GRCh38) [ NCBI UCSC ] 17: 42338066 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 Feb 20, 2024 Aug 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000342.4:c.286C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000333.1:p.Arg96Cys missense NC_000017.11:g.44260698G>A NC_000017.10:g.42338066G>A NG_007498.1:g.12437C>T LRG_803:g.12437C>T LRG_803t1:c.286C>T LRG_803p1:p.Arg96Cys - Protein change
- R96C
- Other names
- -
- Canonical SPDI
- NC_000017.11:44260697:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SLC4A1 | - | - |
GRCh38 GRCh37 |
672 | 682 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 4, 2020 | RCV000275834.8 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000334118.5 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000386246.5 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Aug 16, 2023 | RCV001355054.10 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely benign
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spherocytosis type 4
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000403297.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Benign
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant distal renal tubular acidosis
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000403295.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Likely benign
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hemolytic anemia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000403296.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Uncertain significance
(Jun 04, 2020)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant distal renal tubular acidosis
Affected status: unknown
Allele origin:
inherited
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002097951.1 First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022 |
Comment:
The inherited heterozygous p.Arg96Cys variant identified in SLC4A1 has been reported in one individual affected with non-recurrent nephrolithiasis [PMID: 30778725]. The patient was heterozygous for … (more)
The inherited heterozygous p.Arg96Cys variant identified in SLC4A1 has been reported in one individual affected with non-recurrent nephrolithiasis [PMID: 30778725]. The patient was heterozygous for the p.Arg96Cys variant and had a familyhistory positive for nephrolithiasis [PMID: 30778725]. The p.Arg96Cys variant has 0.0000698 allele frequency (10 out of 143,260 heterozygous alleles, no homozygotes) in gnomAD(v3) database indicating it is a rare allele in the populations represented in the database. The affected residueis not well conserved. In silico prediction tools provide conflicting interpretatons about potential pathogenicityof this variant. Functional studies to evaluate the effect of this variant on normal functioning of the protein have not been reported in the literature. Based on the current evidence, the inherited p.Arg96Cys variant in the SLC4A1 gene is classified as a variant of uncertain significance. (less)
Clinical Features:
Seizure (present) , Specific learning disability (present) , Attention deficit hyperactivity disorder (present) , Hematuria (present) , Nephrolithiasis (present) , Pituitary adenoma (present)
Secondary finding: no
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Uncertain significance
(Aug 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003821429.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely benign
(Jan 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002461849.3
First in ClinVar: Apr 08, 2022 Last updated: Feb 20, 2024 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549820.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The SLC4A1 p.R96C variant was identified in a heterozygous individual with nephrolithiasis (Amar_2019_PMID: 30778725). The variant was identified in dbSNP (ID: rs538778224) and ClinVar (classified … (more)
The SLC4A1 p.R96C variant was identified in a heterozygous individual with nephrolithiasis (Amar_2019_PMID: 30778725). The variant was identified in dbSNP (ID: rs538778224) and ClinVar (classified as likely benign/benign by Illumina). The variant was identified in control databases in 73 of 251312 chromosomes at a frequency of 0.0002905, and was observed at the highest frequency in the South Asian population in 72 of 30616 chromosomes (freq: 0.002352) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.R96 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs538778224 ...
HelpRecord last updated Mar 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.