Genetic Variant NM_002976.4:c.122C>T (chr2-166477575-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002976.4(SCN7A):c.122C>T(p.Thr41Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 151,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T41N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SCN7A
NM_002976.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.070706725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN7A	NM_002976.4 link	c.122C>T	p.Thr41Ile	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>T	p.Thr41Ile	missense_variant	Exon 3 of 26		NM_002976.4	ENSP00000496114.1		Q01118

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151660

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000491

AC:

AN:

203490

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000815

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.99e-7

AC:

AN:

1430780

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708638

show subpopulations

African (AFR)

AF:

0.0000303

AC:

AN:

32958

American (AMR)

AF:

0.00

AC:

AN:

39972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25528

East Asian (EAS)

AF:

0.00

AC:

AN:

38892

South Asian (SAS)

AF:

0.00

AC:

AN:

82326

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51776

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094424

Other (OTH)

AF:

0.00

AC:

AN:

59184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000198

AC:

AN:

151660

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74036

show subpopulations

African (AFR)

AF:

0.0000726

AC:

AN:

41320

American (AMR)

AF:

0.00

AC:

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67810

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

56508

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.26

CADD

Benign

8.1

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

T;T;T;T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.054

LIST_S2

Uncertain

0.86

.;D;.;.;.;D

M_CAP

Benign

0.035

MetaRNN

Benign

0.071

T;T;T;T;T;T

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

0.0

N;N;N;N;N;.

PhyloP100

-0.19

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.3

.;.;N;.;D;N

REVEL

Benign

0.18

Sift

Uncertain

0.0030

.;.;D;.;D;D

Sift4G

Uncertain

0.017

D;D;D;.;.;D

Polyphen

0.010

B;B;B;B;B;.

Vest4

0.048

MutPred

0.26

Loss of glycosylation at T41 (P = 0.0125);Loss of glycosylation at T41 (P = 0.0125);Loss of glycosylation at T41 (P = 0.0125);Loss of glycosylation at T41 (P = 0.0125);Loss of glycosylation at T41 (P = 0.0125);Loss of glycosylation at T41 (P = 0.0125);

MVP

0.61

MPC

0.035

ClinPred

0.047

GERP RS

1.1

Varity_R

0.057

gMVP

0.11

Mutation Taster

=99/1

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over