2-166405696-C-A

Position:

chr2-166405696-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_002976.4(SCN7A):c.4933G>T(p.Asp1645Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,612,844 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

SCN7A
NM_002976.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.255

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:

SCN7A (HGNC:):

SCN7A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17350546).

BP6

Variant 2-166405696-C-A is Benign according to our data. Variant chr2-166405696-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1148518.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN7A	NM_002976.4 linkuse as main transcript	c.4933G>T	p.Asp1645Tyr	missense_variant	26/26	ENST00000643258.1	NP_002967.2	Q01118

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN7A	ENST00000643258.1 linkuse as main transcript	c.4933G>T	p.Asp1645Tyr	missense_variant	26/26		NM_002976.4	ENSP00000496114.1	Q01118
SCN7A	ENST00000441411.2 linkuse as main transcript	c.4933G>T	p.Asp1645Tyr	missense_variant	25/25	1		ENSP00000403846.2	Q01118
SCN7A	ENST00000424326.5 linkuse as main transcript	n.*2738G>T		non_coding_transcript_exon_variant	26/26	1		ENSP00000396600.1	F8WD82
SCN7A	ENST00000424326.5 linkuse as main transcript	n.*2738G>T		3_prime_UTR_variant	26/26	1		ENSP00000396600.1	F8WD82

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000685

AC:

AN:

248274

Hom.:

AF XY:

0.0000965

AC XY:

AN XY:

134694

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1460822

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

726708

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.23

DEOGEN2

Benign

0.18

T;T;T;T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.54

.;T;.;.;.

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.17

T;T;T;T;T

MetaSVM

Uncertain

0.54

MutationAssessor

Uncertain

2.1

M;M;M;M;M

PrimateAI

Benign

0.35

PROVEAN

Benign

0.010

.;.;N;.;.

REVEL

Uncertain

0.31

Sift

Benign

0.038

.;.;D;.;.

Sift4G

Benign

0.13

T;T;T;.;.

Polyphen

0.015

B;B;B;B;B

Vest4

0.29

MutPred

0.42

Loss of ubiquitination at K1646 (P = 0.0219);Loss of ubiquitination at K1646 (P = 0.0219);Loss of ubiquitination at K1646 (P = 0.0219);Loss of ubiquitination at K1646 (P = 0.0219);Loss of ubiquitination at K1646 (P = 0.0219);

MVP

0.93

MPC

0.042

ClinPred

0.078

GERP RS

3.9

Varity_R

0.075

gMVP

0.38

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