17-8161759-TCCA-T

Position:

• chr17-8161759-TCCA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_014232.3(VAMP2):​c.128_130del​(p.Val43del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAMP2 NM_014232.3 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32

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 7 ACMG points.

• PM1: In a domain v-SNARE coiled-coil homology (size 60) in uniprot entity VAMP2_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_014232.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_014232.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-8161759-TCCA-T is Pathogenic according to our data. Variant chr17-8161759-TCCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 666257.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-8161759-TCCA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAMP2	NM_014232.3	c.128_130del	p.Val43del	inframe_deletion	3/5	ENST00000316509.11
VAMP2	NM_001330125.1	c.134_136del	p.Val45del	inframe_deletion	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAMP2	ENST00000316509.11	c.128_130del	p.Val43del	inframe_deletion	3/5	1	NM_014232.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 31, 2020

- -

Severe neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory - UDIAT Centre Diagnòstic, Hospital Universitari Parc Tauli

Jul 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1598265441; hg19: chr17-8065077;