Genetic Variant VAMP2:c.*1590T>C (chr17-8159265-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_014232.3(VAMP2):c.*1590T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 151,260 control chromosomes in the GnomAD database, including 34,117 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.67 ( 34105 hom., cov: 27)

Exomes 𝑓: 0.79 ( 12 hom. )

Consequence

VAMP2
NM_014232.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.06

Publications

24 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

VAMP2 links:

ENSG00000263620 (HGNC:):

ENSG00000263620 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAMP2	NM_014232.3 link	c.*1590T>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000316509.11	NP_055047.2	P63027
VAMP2	NM_001330125.1 link	c.*1590T>C		3_prime_UTR_variant	Exon 5 of 5		NP_001317054.1	F8WCA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAMP2	ENST00000316509.11 link	c.*1590T>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_014232.3	ENSP00000314214.6		P63027
ENSG00000263620	ENST00000498285.1 link	c.334+2208T>C		intron_variant	Intron 4 of 4	4		ENSP00000464383.1		L7N2F9

Frequencies

GnomAD3 genomes

AF:

0.669

AC:

101124

AN:

151100

Hom.:

34080

Cov.:

show subpopulations

Gnomad AFR

AF:

0.645

Gnomad AMI

AF:

0.629

Gnomad AMR

AF:

0.698

Gnomad ASJ

AF:

0.491

Gnomad EAS

AF:

0.496

Gnomad SAS

AF:

0.729

Gnomad FIN

AF:

0.780

Gnomad MID

AF:

0.592

Gnomad NFE

AF:

0.680

Gnomad OTH

AF:

0.651

GnomAD4 exome

AF:

0.786

AC:

AN:

Hom.:

Cov.:

AF XY:

0.778

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.765

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.875

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.669

AC:

101194

AN:

151218

Hom.:

34105

Cov.:

AF XY:

0.675

AC XY:

49800

AN XY:

73820

show subpopulations

African (AFR)

AF:

0.645

AC:

26515

AN:

41114

American (AMR)

AF:

0.698

AC:

10594

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.491

AC:

1703

AN:

3470

East Asian (EAS)

AF:

0.497

AC:

2547

AN:

5128

South Asian (SAS)

AF:

0.729

AC:

3493

AN:

4792

European-Finnish (FIN)

AF:

0.780

AC:

8153

AN:

10450

Middle Eastern (MID)

AF:

0.589

AC:

172

AN:

292

European-Non Finnish (NFE)

AF:

0.680

AC:

46092

AN:

67792

Other (OTH)

AF:

0.649

AC:

1358

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1637

3274

4912

6549

8186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

810

1620

2430

3240

4050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.666

Hom.:

48475

Bravo

AF:

0.658

Asia WGS

AF:

0.626

AC:

2177

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over