Variant chr2-166423412-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002976.4(SCN7A):c.2874G>A(p.Met958Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,577,502 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

SCN7A
NM_002976.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.02

Variant links:

Genes affected

SCN7A (HGNC:10594): (sodium voltage-gated channel alpha subunit 7) This gene encodes one of the many voltage-gated sodium channel proteins. For proper functioning of neurons and muscles during action potentials, voltage-gated sodium channels direct sodium ion diffusion for membrane depolarization. This sodium channel protein has some atypical characteristics; the similarity between the human and mouse proteins is lower compared to other orthologous sodium channel pairs. Also, the S4 segments, which sense voltage changes, have fewer positive charged residues that in other sodium channels; domain 4 has fewer arginine and lysine residues compared to other sodium channel proteins. Several alternatively spliced transcript variants exist, but the full-length natures of all of them remain unknown. [provided by RefSeq, Dec 2011]

SCN7A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060328096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN7A	NM_002976.4 linkuse as main transcript	c.2874G>A	p.Met958Ile	missense_variant	19/26	ENST00000643258.1	NP_002967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SCN7A	ENST00000643258.1 linkuse as main transcript	c.2874G>A	p.Met958Ile	missense_variant	19/26		NM_002976.4	ENSP00000496114	P1
SCN7A	ENST00000441411.2 linkuse as main transcript	c.2874G>A	p.Met958Ile	missense_variant	18/25	1		ENSP00000403846	P1
SCN7A	ENST00000424326.5 linkuse as main transcript	c.*679G>A		3_prime_UTR_variant, NMD_transcript_variant	19/26	1		ENSP00000396600

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151704

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000193

AC:

AN:

207238

Hom.:

AF XY:

0.0000178

AC XY:

AN XY:

112280

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000688

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000321

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000168

AC:

AN:

1425798

Hom.:

Cov.:

AF XY:

0.0000226

AC XY:

AN XY:

707894

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000259

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000201

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151704

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74054

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.016

DANN

Benign

0.67

DEOGEN2

Uncertain

0.46

T;T;T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.57

.;T;.;.;.

M_CAP

Benign

0.045

MetaRNN

Benign

0.060

T;T;T;T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

-1.8

N;N;N;N;N

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

2.6

.;.;N;.;.

REVEL

Uncertain

0.34

Sift

Benign

1.0

.;.;T;.;.

Sift4G

Benign

1.0

T;T;T;.;.

Polyphen

0.0

B;B;B;B;B

Vest4

0.090

MutPred

0.52

Loss of phosphorylation at Y957 (P = 0.0825);Loss of phosphorylation at Y957 (P = 0.0825);Loss of phosphorylation at Y957 (P = 0.0825);Loss of phosphorylation at Y957 (P = 0.0825);Loss of phosphorylation at Y957 (P = 0.0825);

MVP

0.55

MPC

0.036

ClinPred

0.031

GERP RS

-1.5

Varity_R

0.065

gMVP

0.096

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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