2-166423412-C-A

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.2874G>T(p.Met958Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.699 in 1,574,744 control chromosomes in the GnomAD database, including 387,363 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.75 ( 43536 hom., cov: 30)

Exomes 𝑓: 0.69 ( 343827 hom. )

Consequence

SCN7A
NM_002976.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -2.02

Publications

38 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=7.526435E-7).

BP6

Variant 2-166423412-C-A is Benign according to our data. Variant chr2-166423412-C-A is described in ClinVar as Benign. ClinVar VariationId is 3059687.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.922 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.2874G>T	p.Met958Ile	missense	Exon 19 of 26	NP_002967.2	Q01118
	SCN7A	NR_045628.1		n.3098G>T		non_coding_transcript_exon	Exon 19 of 26

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN7A	ENST00000643258.1	MANE Select	c.2874G>T	p.Met958Ile	missense	Exon 19 of 26	ENSP00000496114.1	Q01118
SCN7A	ENST00000441411.2	TSL:1	c.2874G>T	p.Met958Ile	missense	Exon 18 of 25	ENSP00000403846.2	Q01118
SCN7A	ENST00000424326.5	TSL:1	n.*679G>T		non_coding_transcript_exon	Exon 19 of 26	ENSP00000396600.1	F8WD82

Frequencies

GnomAD3 genomes

AF:

0.748

AC:

113479

AN:

151630

Hom.:

43476

Cov.:

show subpopulations

Gnomad AFR

AF:

0.930

Gnomad AMI

AF:

0.784

Gnomad AMR

AF:

0.694

Gnomad ASJ

AF:

0.655

Gnomad EAS

AF:

0.668

Gnomad SAS

AF:

0.706

Gnomad FIN

AF:

0.674

Gnomad MID

AF:

0.725

Gnomad NFE

AF:

0.675

Gnomad OTH

AF:

0.745

GnomAD2 exomes

AF:

0.696

AC:

144203

AN:

207238

AF XY:

0.691

show subpopulations

Gnomad AFR exome

AF:

0.929

Gnomad AMR exome

AF:

0.688

Gnomad ASJ exome

AF:

0.678

Gnomad EAS exome

AF:

0.669

Gnomad FIN exome

AF:

0.667

Gnomad NFE exome

AF:

0.675

Gnomad OTH exome

AF:

0.687

GnomAD4 exome

AF:

0.694

AC:

987357

AN:

1422994

Hom.:

343827

Cov.:

AF XY:

0.693

AC XY:

489923

AN XY:

706642

show subpopulations

African (AFR)

AF:

0.938

AC:

29391

AN:

31336

American (AMR)

AF:

0.688

AC:

25459

AN:

37028

Ashkenazi Jewish (ASJ)

AF:

0.672

AC:

16802

AN:

24988

East Asian (EAS)

AF:

0.688

AC:

26554

AN:

38576

South Asian (SAS)

AF:

0.713

AC:

57266

AN:

80276

European-Finnish (FIN)

AF:

0.666

AC:

34833

AN:

52288

Middle Eastern (MID)

AF:

0.737

AC:

4030

AN:

5470

European-Non Finnish (NFE)

AF:

0.687

AC:

751391

AN:

1094272

Other (OTH)

AF:

0.708

AC:

41631

AN:

58760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

13842

27683

41525

55366

69208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19426

38852

58278

77704

97130

<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:

0.749

AC:

113597

AN:

151750

Hom.:

43536

Cov.:

AF XY:

0.746

AC XY:

55276

AN XY:

74140

show subpopulations

African (AFR)

AF:

0.930

AC:

38577

AN:

41490

American (AMR)

AF:

0.693

AC:

10518

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.655

AC:

2265

AN:

3458

East Asian (EAS)

AF:

0.669

AC:

3435

AN:

5136

South Asian (SAS)

AF:

0.705

AC:

3390

AN:

4810

European-Finnish (FIN)

AF:

0.674

AC:

7108

AN:

10540

Middle Eastern (MID)

AF:

0.724

AC:

213

AN:

294

European-Non Finnish (NFE)

AF:

0.675

AC:

45816

AN:

67848

Other (OTH)

AF:

0.747

AC:

1568

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1361

2721

4082

5442

6803

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<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:

0.692

Hom.:

147484

Bravo

AF:

0.759

TwinsUK

AF:

0.697

AC:

2585

ALSPAC

AF:

0.685

AC:

2639

ESP6500AA

AF:

0.929

AC:

3354

ESP6500EA

AF:

0.679

AC:

5559

ExAC

AF:

0.683

AC:

81684

Asia WGS

AF:

0.703

AC:

2441

AN:

3470

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

0.083

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.019

(source)

DANN

Benign

0.55

DEOGEN2

Uncertain

0.46

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.57

MetaRNN

Benign

7.5e-7

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.8

PhyloP100

-2.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

2.6

REVEL

Uncertain

0.35

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.090

MutPred

0.52

Loss of phosphorylation at Y957 (P = 0.0825)

MPC

0.036

ClinPred

0.00030

GERP RS

-1.5

Varity_R

0.065

gMVP

0.096

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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