Variant 2-166405764-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_002976.4(SCN7A):c.4865G>A(p.Arg1622Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,612,850 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 4 hom. )

Consequence

SCN7A
NM_002976.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.38

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:

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=0.016739339).

BP6

Variant 2-166405764-C-T is Benign according to our data. Variant chr2-166405764-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1136974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN7A	NM_002976.4 linkuse as main transcript	c.4865G>A	p.Arg1622Gln	missense_variant	26/26	ENST00000643258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SCN7A	ENST00000643258.1 linkuse as main transcript	c.4865G>A	p.Arg1622Gln	missense_variant	26/26		NM_002976.4	P1
SCN7A	ENST00000441411.2 linkuse as main transcript	c.4865G>A	p.Arg1622Gln	missense_variant	25/25	1		P1
SCN7A	ENST00000424326.5 linkuse as main transcript	c.*2670G>A		3_prime_UTR_variant, NMD_transcript_variant	26/26	1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000788

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00277

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00157

AC:

389

AN:

247602

Hom.:

AF XY:

0.00159

AC XY:

213

AN XY:

134308

show subpopulations

Gnomad AFR exome

AF:

0.000518

Gnomad AMR exome

AF:

0.00117

Gnomad ASJ exome

AF:

0.000601

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00266

Gnomad NFE exome

AF:

0.00232

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.00259

AC:

3781

AN:

1460758

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

1788

AN XY:

726658

show subpopulations

Gnomad4 AFR exome

AF:

0.000539

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.000499

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000244

Gnomad4 FIN exome

AF:

0.00251

Gnomad4 NFE exome

AF:

0.00306

Gnomad4 OTH exome

AF:

0.00237

GnomAD4 genome

AF:

0.00176

AC:

268

AN:

152092

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

134

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.000771

Gnomad4 AMR

AF:

0.000787

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00255

Gnomad4 NFE

AF:

0.00277

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00224

Hom.:

Bravo

AF:

0.00162

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00106

AC:

ESP6500EA

AF:

0.00243

AC:

ExAC

AF:

0.00153

AC:

185

EpiCase

AF:

0.00317

EpiControl

AF:

0.00196

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 28, 2023

- -

SCN7A-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2022

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

0.19

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

T;T;T;T;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.91

M_CAP

Benign

0.078

MetaRNN

Benign

0.017

T;T;T;T;T

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.8

M;M;M;M;M

MutationTaster

Benign

0.93

PrimateAI

Benign

0.38

Sift4G

Benign

0.10

T;T;T;.;.

Polyphen

0.95

P;P;P;P;P

Vest4

0.38

MVP

0.98

MPC

0.12

ClinPred

0.047

GERP RS

3.6

Varity_R

0.18

gMVP

0.54

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