NM_002976.4:c.4786G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_002976.4(SCN7A):c.4786G>C(p.Val1596Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0961 in 1,612,964 control chromosomes in the GnomAD database, including 8,123 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.081 ( 597 hom., cov: 32)

Exomes 𝑓: 0.098 ( 7526 hom. )

Consequence

SCN7A
NM_002976.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.134

Publications

25 publications found

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 Gene-Disease associations (from GenCC):

holoprosencephaly
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

SCN7A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001709193).

BP6

Variant 2-166405843-C-G is Benign according to our data. Variant chr2-166405843-C-G is described in ClinVar as Benign. ClinVar VariationId is 3057148.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002976.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN7A	NM_002976.4	MANE Select	c.4786G>C	p.Val1596Leu	missense	Exon 26 of 26	NP_002967.2	Q01118
	SCN7A	NR_045628.1		n.5010G>C		non_coding_transcript_exon	Exon 26 of 26

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN7A	ENST00000643258.1	MANE Select	c.4786G>C	p.Val1596Leu	missense	Exon 26 of 26	ENSP00000496114.1	Q01118
SCN7A	ENST00000441411.2	TSL:1	c.4786G>C	p.Val1596Leu	missense	Exon 25 of 25	ENSP00000403846.2	Q01118
SCN7A	ENST00000424326.5	TSL:1	n.*2591G>C		non_coding_transcript_exon	Exon 26 of 26	ENSP00000396600.1	F8WD82

Frequencies

GnomAD3 genomes

AF:

0.0813

AC:

12348

AN:

151938

Hom.:

597

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0469

Gnomad AMI

AF:

0.0691

Gnomad AMR

AF:

0.0505

Gnomad ASJ

AF:

0.156

Gnomad EAS

AF:

0.125

Gnomad SAS

AF:

0.134

Gnomad FIN

AF:

0.0858

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.0969

Gnomad OTH

AF:

0.0964

GnomAD2 exomes

AF:

0.0958

AC:

23746

AN:

247866

AF XY:

0.0996

show subpopulations

Gnomad AFR exome

AF:

0.0439

Gnomad AMR exome

AF:

0.0454

Gnomad ASJ exome

AF:

0.169

Gnomad EAS exome

AF:

0.130

Gnomad FIN exome

AF:

0.0903

Gnomad NFE exome

AF:

0.0974

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.0976

AC:

142611

AN:

1460908

Hom.:

7526

Cov.:

AF XY:

0.0993

AC XY:

72166

AN XY:

726738

show subpopulations

African (AFR)

AF:

0.0441

AC:

1475

AN:

33420

American (AMR)

AF:

0.0488

AC:

2180

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

4377

AN:

26092

East Asian (EAS)

AF:

0.138

AC:

5460

AN:

39692

South Asian (SAS)

AF:

0.129

AC:

11148

AN:

86230

European-Finnish (FIN)

AF:

0.0912

AC:

4868

AN:

53384

Middle Eastern (MID)

AF:

0.177

AC:

1020

AN:

5760

European-Non Finnish (NFE)

AF:

0.0951

AC:

105636

AN:

1111346

Other (OTH)

AF:

0.107

AC:

6447

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

7241

14481

21722

28962

36203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3952

7904

11856

15808

19760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0812

AC:

12345

AN:

152056

Hom.:

597

Cov.:

AF XY:

0.0798

AC XY:

5932

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.0468

AC:

1943

AN:

41534

American (AMR)

AF:

0.0504

AC:

769

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.156

AC:

541

AN:

3464

East Asian (EAS)

AF:

0.125

AC:

645

AN:

5148

South Asian (SAS)

AF:

0.133

AC:

641

AN:

4824

European-Finnish (FIN)

AF:

0.0858

AC:

909

AN:

10598

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0969

AC:

6585

AN:

67930

Other (OTH)

AF:

0.0991

AC:

209

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

581

1163

1744

2326

2907

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<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:

0.102

Hom.:

615

Bravo

AF:

0.0773

TwinsUK

AF:

0.103

AC:

383

ALSPAC

AF:

0.0944

AC:

364

ESP6500AA

AF:

0.0444

AC:

167

ESP6500EA

AF:

0.0976

AC:

803

ExAC

AF:

0.0965

AC:

11661

Asia WGS

AF:

0.123

AC:

428

AN:

3478

EpiCase

AF:

0.102

EpiControl

AF:

0.100

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

SCN7A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.20

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.77

MutationAssessor

Benign

-1.9

PhyloP100

-0.13

PrimateAI

Benign

0.29

PROVEAN

Benign

0.71

REVEL

Benign

0.26

Sift

Benign

0.34

Sift4G

Benign

0.27

Polyphen

0.0

Vest4

0.015

MPC

0.033

ClinPred

0.00049

GERP RS

1.6

Varity_R

0.029

gMVP

0.17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over