VCV001791620.2 - ClinVar

NM_000100.4(CSTB):c.246_247del (p.Leu82fs)

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.

(1)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000100.4(CSTB):c.246_247del (p.Leu82fs)

Variation ID: 1791620 Accession: VCV001791620.2

Type and length

Deletion, 2 bp

Location

Cytogenetic: 21q22.3 21: 43774252-43774253 (GRCh38) [ NCBI UCSC ] 21: 45194133-45194134 (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	Nov 29, 2022	May 1, 2024	Sep 11, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_000100.4:c.246_247del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000091.1:p.Leu82fs	frameshift
NC_000021.9:g.43774253_43774254del
NC_000021.8:g.45194134_45194135del
NG_011545.1:g.7126_7127del
LRG_485:g.7126_7127del
LRG_485t1:c.245_246del	LRG_485p1:p.Leu82Phefs

... more HGVS ... less HGVS

Protein change

L82fs

Other names

Canonical SPDI

NC_000021.9:43774251:ATA:A

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.
CSTB		-	-	GRCh38 GRCh37	112	280

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.
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Sep 11, 2017	RCV002455478.2

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.
Likely pathogenic (Sep 11, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002738203.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 17217964‚ 2347312 Comment: The c.246_247delAT variant, located in coding exon 3 of the CSTB gene, results from a deletion of two nucleotides at nucleotide positions 246 to 247, … (more) The c.246_247delAT variant, located in coding exon 3 of the CSTB gene, results from a deletion of two nucleotides at nucleotide positions 246 to 247, causing a translational frameshift with a predicted alternate stop codon (p.L82Ffs*2). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus and is not expected to trigger nonsense-mediated mRNA decay. This variant impacts the last 17 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. This protein truncation is indicated to be structurally destabilizing and to disrupt binding of target proteins (Ambry internal data; Stubbs MT et al. EMBO J., 1990 Jun;9:1939-47; Jenko Kokalj S et al. J. Mol. Biol., 2007 Mar;366:1569-79). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)

Comment:

The c.246_247delAT variant, located in coding exon 3 of the CSTB gene, results from a deletion of two nucleotides at nucleotide positions 246 to 247, causing a translational frameshift with a predicted alternate stop codon (p.L82Ffs*2). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus and is not expected to trigger nonsense-mediated mRNA decay. This variant impacts the last 17 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. This protein truncation is indicated to be structurally destabilizing and to disrupt binding of target proteins (Ambry internal data; Stubbs MT et al. EMBO J., 1990 Jun;9:1939-47; Jenko Kokalj S et al. J. Mol. Biol., 2007 Mar;366:1569-79). Based on the majority of available evidence to date, this variant is likely to be 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
Essential role of proline isomerization in stefin B tetramer formation.	Jenko Kokalj S	Journal of molecular biology	2007	PMID: 17217964
The refined 2.4 A X-ray crystal structure of recombinant human stefin B in complex with the cysteine proteinase papain: a novel type of proteinase inhibitor interaction.	Stubbs MT	The EMBO journal	1990	PMID: 2347312

Text-mined citations for this variant ...

Record last updated May 01, 2024

ClinVar Genomic variation as it relates to human health

NM_000100.4(CSTB):c.246_247del (p.Leu82fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...