2-166477575-G-T

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.122C>A(p.Thr41Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 1,582,236 control chromosomes in the GnomAD database, including 375,869 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 0.70 ( 36788 hom., cov: 31)

Exomes 𝑓: 0.69 ( 339081 hom. )

Consequence

SCN7A
NM_002976.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.187

Publications

40 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 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=1.1589253E-6).

BP6

Variant 2-166477575-G-T is Benign according to our data. Variant chr2-166477575-G-T is described in ClinVar as Benign. ClinVar VariationId is 3060194.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN7A	NM_002976.4 link	c.122C>A	p.Thr41Asn	missense_variant	Exon 3 of 26	ENST00000643258.1	NP_002967.2	Q01118

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN7A	ENST00000643258.1 link	c.122C>A	p.Thr41Asn	missense_variant	Exon 3 of 26		NM_002976.4	ENSP00000496114.1		Q01118

Frequencies

GnomAD3 genomes

AF:

0.695

AC:

105360

AN:

151596

Hom.:

36751

Cov.:

show subpopulations

Gnomad AFR

AF:

0.747

Gnomad AMI

AF:

0.784

Gnomad AMR

AF:

0.668

Gnomad ASJ

AF:

0.656

Gnomad EAS

AF:

0.674

Gnomad SAS

AF:

0.702

Gnomad FIN

AF:

0.674

Gnomad MID

AF:

0.718

Gnomad NFE

AF:

0.674

Gnomad OTH

AF:

0.706

GnomAD2 exomes

AF:

0.684

AC:

139247

AN:

203490

AF XY:

0.683

show subpopulations

Gnomad AFR exome

AF:

0.741

Gnomad AMR exome

AF:

0.677

Gnomad ASJ exome

AF:

0.677

Gnomad EAS exome

AF:

0.678

Gnomad FIN exome

AF:

0.666

Gnomad NFE exome

AF:

0.678

Gnomad OTH exome

AF:

0.682

GnomAD4 exome

AF:

0.688

AC:

984609

AN:

1430520

Hom.:

339081

Cov.:

AF XY:

0.688

AC XY:

487716

AN XY:

708490

show subpopulations

African (AFR)

AF:

0.748

AC:

24646

AN:

32948

American (AMR)

AF:

0.675

AC:

26965

AN:

39940

Ashkenazi Jewish (ASJ)

AF:

0.673

AC:

17190

AN:

25524

East Asian (EAS)

AF:

0.693

AC:

26941

AN:

38886

South Asian (SAS)

AF:

0.710

AC:

58433

AN:

82294

European-Finnish (FIN)

AF:

0.666

AC:

34487

AN:

51770

Middle Eastern (MID)

AF:

0.719

AC:

4113

AN:

5718

European-Non Finnish (NFE)

AF:

0.686

AC:

750554

AN:

1094272

Other (OTH)

AF:

0.698

AC:

41280

AN:

59168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

17670

35339

53009

70678

88348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19476

38952

58428

77904

97380

<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:

0.695

AC:

105447

AN:

151716

Hom.:

36788

Cov.:

AF XY:

0.693

AC XY:

51392

AN XY:

74132

show subpopulations

African (AFR)

AF:

0.747

AC:

30959

AN:

41434

American (AMR)

AF:

0.667

AC:

10152

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.656

AC:

2267

AN:

3458

East Asian (EAS)

AF:

0.676

AC:

3486

AN:

5160

South Asian (SAS)

AF:

0.701

AC:

3376

AN:

4818

European-Finnish (FIN)

AF:

0.674

AC:

7113

AN:

10548

Middle Eastern (MID)

AF:

0.718

AC:

211

AN:

294

European-Non Finnish (NFE)

AF:

0.674

AC:

45687

AN:

67786

Other (OTH)

AF:

0.707

AC:

1484

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1659

3318

4976

6635

8294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

824

1648

2472

3296

4120

<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:

0.675

Hom.:

56508

Bravo

AF:

0.699

TwinsUK

AF:

0.697

AC:

2585

ALSPAC

AF:

0.683

AC:

2631

ESP6500AA

AF:

0.752

AC:

2755

ESP6500EA

AF:

0.679

AC:

5540

ExAC

AF:

0.657

AC:

78042

Asia WGS

AF:

0.692

AC:

2404

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

SCN7A-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

0.049

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.13

(source)

DANN

Benign

0.096

DEOGEN2

Benign

0.18

T;T;T;T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0056

LIST_S2

Benign

0.50

.;T;.;.;.;T

MetaRNN

Benign

0.0000012

T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.8

N;N;N;N;N;.

PhyloP100

-0.19

PrimateAI

Benign

0.24

PROVEAN

Benign

2.2

.;.;N;.;N;N

REVEL

Benign

0.20

Sift

Benign

1.0

.;.;T;.;T;T

Sift4G

Benign

1.0

T;T;T;.;.;T

Polyphen

0.0

B;B;B;B;B;.

Vest4

0.021

MPC

0.037

ClinPred

0.0049

GERP RS

1.1

Varity_R

0.022

gMVP

0.040

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over