17-8160864-GAAGTA-G

Position:

• chr17-8160864-GAAGTA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_014232.3(VAMP2):​c.337_341del​(p.Tyr113GlnfsTer12) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: VAMP2 NM_014232.3 frameshift, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.02

Genes affected

VAMP2 (HGNC:12643): (vesicle associated membrane protein 2) The protein encoded by this gene is a member of the vesicle-associated membrane protein (VAMP)/synaptobrevin family. Synaptobrevins/VAMPs, syntaxins, and the 25-kD synaptosomal-associated protein SNAP25 are the main components of a protein complex involved in the docking and/or fusion of synaptic vesicles with the presynaptic membrane. This gene is thought to participate in neurotransmitter release at a step between docking and fusion. The protein forms a stable complex with syntaxin, synaptosomal-associated protein, 25 kD, and synaptotagmin. It also forms a distinct complex with synaptophysin. It is a likely candidate gene for familial infantile myasthenia (FIMG) because of its map location and because it encodes a synaptic vesicle protein of the type that has been implicated in the pathogenesis of FIMG. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0399 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-8160864-GAAGTA-G is Pathogenic according to our data. Variant chr17-8160864-GAAGTA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 929464.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAMP2	NM_014232.3	c.337_341del	p.Tyr113GlnfsTer12	frameshift_variant, splice_region_variant	5/5	ENST00000316509.11
VAMP2	NM_001330125.1	c.343_347del	p.Tyr115GlnfsTer12	frameshift_variant, splice_region_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAMP2	ENST00000316509.11	c.337_341del	p.Tyr113GlnfsTer12	frameshift_variant, splice_region_variant	5/5	1	NM_014232.3	P1
VAMP2	ENST00000488857.5	c.343_347del	p.Tyr115GlnfsTer12	frameshift_variant, splice_region_variant	5/5	3
VAMP2	ENST00000404970.3	c.*596_*600del		3_prime_UTR_variant	4/4	2
VAMP2	ENST00000711100.1	c.*358_*362del		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	5/5

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2020

Observed as a de novo variant in internal GeneDx whole exome sequencing data in association with global developmental delay and behavioral issues. Frameshift variant in which the last 4 amino acids are replaced with 11 different amino acids, although pathogenic variants have not been reported downstream of this position in the protein. Not observed in large population cohorts (Lek et al., 2016). We interpret c.337_341delTACTT as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1983290330; hg19: chr17-8064182;