17-8161723-C-A

Position:

• chr17-8161723-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_014232.3(VAMP2):​c.167G>T​(p.Arg56Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAMP2 NM_014232.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.90

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]

ENSG00000263620 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant 17-8161723-C-A is Pathogenic according to our data. Variant chr17-8161723-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 929463.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VAMP2	NM_014232.3	c.167G>T	p.Arg56Leu	missense_variant	3/5	ENST00000316509.11	NP_055047.2
VAMP2	NM_001330125.1	c.173G>T	p.Arg58Leu	missense_variant	3/5		NP_001317054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAMP2	ENST00000316509.11	c.167G>T	p.Arg56Leu	missense_variant	3/5	1	NM_014232.3	ENSP00000314214.6
ENSG00000263620	ENST00000498285.1	c.167G>T	p.Arg56Leu	missense_variant	3/5	4		ENSP00000464383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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 intellectual disability and seizures . In silico analysis supports that this missense variant has a deleterious effect on protein structure/function. Not observed in large population cohorts (Lek et al., 2016). We interpret R56L as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	4.8	.;H;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.0	.;D;.;D;.
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	.;D;.;D;.
Sift4G	Uncertain	0.0020	.;.;D;D;.
Polyphen		1.0	.;D;.;.;.
Vest4		0.88, 0.89, 0.88, 0.86
MutPred		0.73		Loss of ubiquitination at K59 (P = 0.0563);Loss of ubiquitination at K59 (P = 0.0563);.;.;Loss of ubiquitination at K59 (P = 0.0563);
MVP		0.73
MPC		3.4
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.97
gMVP		1.0

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: rs1983318892; hg19: chr17-8065041;