VCV003245999.1 - ClinVar

NC_000006.11:g.(?_32796632)_(32808844_?)del

Germline

Classification

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.

(2)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000006.11:g.(?_32796632)_(32808844_?)del

Variation ID: 3245999 Accession: VCV003245999.1

Type and length

Deletion, 12,213 bp

Location

Cytogenetic: 6p21.32 6: 32796632-32808844 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jun 30, 2024	Jun 29, 2024	Oct 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NC_000006.11:g.(?_32796632)_(32808844_?)del

Protein change

Other names

Canonical SPDI

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

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
Gene	OMIM	HI score Help 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.
PSMB8		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	214	231
TAP2		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	359	429

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.
MHC class I deficiency	Pathogenic (1)	criteria provided, single submitter	Oct 5, 2023	RCV004578642.2
Proteosome-associated autoinflammatory syndrome	Uncertain significance (1)	criteria provided, single submitter	Mar 10, 2023	RCV004578643.2

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.
Uncertain significance (Mar 10, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Proteosome-associated autoinflammatory syndrome Affected status: unknown Allele origin: unknown	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV005066144.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Comment: In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more) In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with PSMB8-related conditions. This variant is a gross deletion of the genomic region encompassing exon(s) 6 of the PSMB8 gene, which includes the termination codon. This deletion extends beyond the assayed region for this gene and therefore may encompass additional genes. While this deletion is not anticipated to lead to nonsense mediated decay, it is expected to alter mRNA translation or result in a truncated protein product. (less)
Pathogenic (Oct 05, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	MHC class I deficiency Affected status: unknown Allele origin: unknown	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV005066158.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Publications: PubMed (4) PubMed: 7517574‚ 11529920‚ 12067308‚ 23662797 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the TAP2 gene has been identified. Loss-of-function variants in TAP2 are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the TAP2 gene has been identified. Loss-of-function variants in TAP2 are known to be pathogenic (PMID: 7517574, 11529920, 12067308, 23662797). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals affected with TAP2-related conditions. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with PSMB8-related conditions. This variant is a gross deletion of the genomic region encompassing exon(s) 6 of the PSMB8 gene, which includes the termination codon. This deletion extends beyond the assayed region for this gene and therefore may encompass additional genes. While this deletion is not anticipated to lead to nonsense mediated decay, it is expected to alter mRNA translation or result in a truncated protein product.

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the TAP2 gene has been identified. Loss-of-function variants in TAP2 are known to be pathogenic (PMID: 7517574, 11529920, 12067308, 23662797). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals affected with TAP2-related conditions. For these reasons, this variant has been classified as Pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Transporter associated with antigen processing deficiency syndrome: case report of an adolescent with chronic perforated granulomatous skin lesions due to TAP2 mutation.	Konstantinou P	Pediatric dermatology	2013	PMID: 23662797
Asymptomatic deficiency in the peptide transporter associated to antigen processing (TAP).	de la Salle H	Clinical and experimental immunology	2002	PMID: 12067308
Molecular studies and NK cell function of a new case of TAP2 homozygous human deficiency.	Matamoros N	Clinical and experimental immunology	2001	PMID: 11529920
Homozygous human TAP peptide transporter mutation in HLA class I deficiency.	de la Salle H	Science (New York, N.Y.)	1994	PMID: 7517574

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NC_000006.11:g.(?_32796632)_(32808844_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...