chr17-8161693-C-T

Variant names:

• chr17-8161693-C-T
• NM_014232.3:c.197G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP3

The NM_014232.3(VAMP2):​c.197G>A​(p.Arg66His) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R66P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAMP2 NM_014232.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90
• Publications: 0 publications found

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]

VAMP2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000263620 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a domain v-SNARE coiled-coil homology (size 60) in uniprot entity VAMP2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_014232.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-8161693-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 4055786.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.4131 (below the threshold of 3.09). Trascript score misZ: 1.7432 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014232.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAMP2	NM_014232.3	MANE Select	c.197G>A	p.Arg66His	missense	Exon 3 of 5	NP_055047.2	P63027
	VAMP2	NM_001330125.1		c.203G>A	p.Arg68His	missense	Exon 3 of 5	NP_001317054.1	F8WCA0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAMP2	ENST00000316509.11	TSL:1 MANE Select	c.197G>A	p.Arg66His	missense	Exon 3 of 5	ENSP00000314214.6	P63027
	ENSG00000263620	ENST00000498285.1	TSL:4	c.197G>A	p.Arg66His	missense	Exon 3 of 5	ENSP00000464383.1	L7N2F9
	VAMP2	ENST00000488857.5	TSL:3	c.203G>A	p.Arg68His	missense	Exon 3 of 5	ENSP00000418572.1	F8WCA0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.64		Loss of stability (P = 0.1023)
MVP		0.54
MPC		3.4
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.98
Mutation Taster		=48/52	disease causing

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

Other links and lift over

hg19: chr17-8065011;