chr2-166406082-C-T

Position:

chr2-166406082-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002976.4(SCN7A):c.4547G>A(p.Arg1516Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00658 in 1,612,390 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0045 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0068 ( 46 hom. )

Consequence

SCN7A
NM_002976.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.77

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:

SCN7A (HGNC:):

SCN7A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068476796).

BP6

Variant 2-166406082-C-T is Benign according to our data. Variant chr2-166406082-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 709139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166406082-C-T is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN7A	NM_002976.4 linkuse as main transcript	c.4547G>A	p.Arg1516Lys	missense_variant	26/26	ENST00000643258.1	NP_002967.2	Q01118

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN7A	ENST00000643258.1 linkuse as main transcript	c.4547G>A	p.Arg1516Lys	missense_variant	26/26		NM_002976.4	ENSP00000496114.1	Q01118
SCN7A	ENST00000441411.2 linkuse as main transcript	c.4547G>A	p.Arg1516Lys	missense_variant	25/25	1		ENSP00000403846.2	Q01118
SCN7A	ENST00000424326.5 linkuse as main transcript	n.*2352G>A		non_coding_transcript_exon_variant	26/26	1		ENSP00000396600.1	F8WD82
SCN7A	ENST00000424326.5 linkuse as main transcript	n.*2352G>A		3_prime_UTR_variant	26/26	1		ENSP00000396600.1	F8WD82

Frequencies

GnomAD3 genomes

AF:

0.00448

AC:

681

AN:

151844

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.0220

Gnomad AMR

AF:

0.000592

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00826

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00376

AC:

927

AN:

246420

Hom.:

AF XY:

0.00389

AC XY:

520

AN XY:

133800

show subpopulations

Gnomad AFR exome

AF:

0.00104

Gnomad AMR exome

AF:

0.00105

Gnomad ASJ exome

AF:

0.000800

Gnomad EAS exome

AF:

0.0000563

Gnomad SAS exome

AF:

0.000819

Gnomad FIN exome

AF:

0.00303

Gnomad NFE exome

AF:

0.00679

Gnomad OTH exome

AF:

0.00353

GnomAD4 exome

AF:

0.00680

AC:

9930

AN:

1460428

Hom.:

Cov.:

AF XY:

0.00661

AC XY:

4800

AN XY:

726470

show subpopulations

Gnomad4 AFR exome

AF:

0.000987

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.000613

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000997

Gnomad4 FIN exome

AF:

0.00396

Gnomad4 NFE exome

AF:

0.00831

Gnomad4 OTH exome

AF:

0.00486

GnomAD4 genome

AF:

0.00448

AC:

681

AN:

151962

Hom.:

Cov.:

AF XY:

0.00408

AC XY:

303

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.000591

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00283

Gnomad4 NFE

AF:

0.00826

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00611

Hom.:

Bravo

AF:

0.00437

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00745

AC:

ExAC

AF:

0.00382

AC:

461

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

SCN7A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;T;T;T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.76

.;T;.;.;.

M_CAP

Benign

0.0041

MetaRNN

Benign

0.0068

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L;L;L;L

PrimateAI

Benign

0.29

PROVEAN

Benign

0.28

.;.;N;.;.

REVEL

Benign

0.042

Sift

Uncertain

0.025

.;.;D;.;.

Sift4G

Uncertain

0.0050

D;D;D;.;.

Polyphen

0.0020

B;B;B;B;B

Vest4

0.12

MVP

0.32

MPC

0.035

ClinPred

0.016

GERP RS

1.3

Varity_R

0.073

gMVP

0.45

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over