Variant 2-165323423-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001040142.2(SCN2A):c.1939G>T(p.Ala647Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A647T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SCN2A
NM_001040142.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.54

Variant links:

Genes affected

SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

SCN2A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, SCN2A

BP4

Computational evidence support a benign effect (MetaRNN=0.09981066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2 linkuse as main transcript	c.1939G>T	p.Ala647Ser	missense_variant	12/27	ENST00000375437.7
SCN2A	NM_001371246.1 linkuse as main transcript	c.1939G>T	p.Ala647Ser	missense_variant	12/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7 linkuse as main transcript	c.1939G>T	p.Ala647Ser	missense_variant	12/27	5	NM_001040142.2	P1	Q99250-1
SCN2A	ENST00000631182.3 linkuse as main transcript	c.1939G>T	p.Ala647Ser	missense_variant	12/27	5	NM_001371246.1		Q99250-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

T;.;T;.;T;T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.0053

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.76

T;.;T;.;.;.;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.10

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

0.14

N;N;.;N;N;N;N

MutationTaster

Benign

0.97

D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.78

N;.;.;.;.;N;N

REVEL

Benign

0.19

Sift

Benign

0.15

T;.;.;.;.;T;T

Sift4G

Benign

0.95

T;.;.;T;.;T;T

Polyphen

0.0050

B;B;.;B;B;B;B

Vest4

0.21

MutPred

0.34

Gain of disorder (P = 0.0202);Gain of disorder (P = 0.0202);.;Gain of disorder (P = 0.0202);Gain of disorder (P = 0.0202);Gain of disorder (P = 0.0202);Gain of disorder (P = 0.0202);

MVP

0.60

ClinPred

0.22

GERP RS

4.7

Varity_R

0.057

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over