NM_005186.4(CAPN1):c.1605+5G>A AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 4, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001547189.17

Allele description [Variation Report for NM_005186.4(CAPN1):c.1605+5G>A]

NM_005186.4(CAPN1):c.1605+5G>A

Gene:

CAPN1:calpain 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.1

Genomic location:

Preferred name:

NM_005186.4(CAPN1):c.1605+5G>A

HGVS:

NC_000011.10:g.65206824G>A
NG_052817.1:g.30610G>A
NM_001198868.2:c.1605+5G>A
NM_001198869.2:c.1605+5G>A
NM_005186.4:c.1605+5G>AMANE SELECT
NC_000011.9:g.64974295G>A
NM_001198868.1:c.1605+5G>A
NM_005186.3:c.1605+5G>A

Nucleotide change:

IVS14DS, G-A, +5

Links:

OMIM: 114220.0004; dbSNP: rs375817528

NCBI 1000 Genomes Browser:

rs375817528

Molecular consequence:

NM_001198868.2:c.1605+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001198869.2:c.1605+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_005186.4:c.1605+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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tz04h04.x1 NCI_CGAP_Ut1 Homo sapiens cDNA clone IMAGE:2287639 3', mRNA sequence
tz04h04.x1 NCI_CGAP_Ut1 Homo sapiens cDNA clone IMAGE:2287639 3', mRNA sequence
gi|5632170|gnl|dbEST|3034281|gb|AI9 .1|

Nucleotide
txid72036[orgn] AND "isolate LsFoM4"[All Fields] (4)
PopSet
Alligator mississippiensis
Alligator mississippiensis
RNA-seq analysis of alligator gonad during sex determination

BioProject
cytochrome P450 [Anopheles funestus]
cytochrome P450 [Anopheles funestus]
gi|2098512649|gb|UBF41923.1|

Protein
Gene-trap donor vector pZGl, complete sequence
Gene-trap donor vector pZGl, complete sequence
gi|148807245|gb|EF591488.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001766837	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 6, 2022)	germline	clinical testing	Citation Link,
SCV002064337	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 4, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002143741	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 32214227, 33486633, 17576681, 9536098, 27153400, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001766837

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Feb 6, 2022)

germline

clinical testing

Citation Link,

SCV002064337

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 4, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002143741

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 4, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery.

Hengel H, Buchert R, Sturm M, Haack TB, Schelling Y, Mahajnah M, Sharkia R, Azem A, Balousha G, Ghanem Z, Falana M, Balousha O, Ayesh S, Keimer R, Deigendesch W, Zaidan J, Marzouqa H, Bauer P, Schöls L.

Eur J Hum Genet. 2020 Aug;28(8):1034-1043. doi: 10.1038/s41431-020-0609-9. Epub 2020 Mar 25. Erratum in: Eur J Hum Genet. 2022 Feb;30(2):248.

PubMed [citation]

PMID:: 32214227
PMCID:: PMC7382450

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV001766837.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Non-canonical splice site variant demonstrated to result in loss-of-function (Gan-Or et al., 2016); This variant is associated with the following publications: (PMID: 30572172, 27153400, 32214227, 33726816, 33486633)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002064337.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

DNA sequence analysis of the CAPN1 gene demonstrated a sequence change located near the canonical splice donor site in intron 14, c.1605+5G>A. This sequence change has been described in the gnomAD database with a low population frequency of 0.012% (dbSNP rs375817528). This variant was identified in two symptomatic family members with spastic paraplegia in a compound heterozygous state with other frameshift variant (Gan-Or et al., 2016). Based on in silico splice prediction programs, this sequence change likely affects normal splicing of the CAPN1 gene, which would result in an abnormal protein, however functional studies have not been performed to prove this conclusively.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002143741.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change falls in intron 14 of the CAPN1 gene. It does not directly change the encoded amino acid sequence of the CAPN1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs375817528, gnomAD 0.02%). This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 27153400, 32214227, 33486633; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225768). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 14 and introduces a premature termination codon (PMID: 27153400). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2024

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