Variant 2-166406062-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002976.4(SCN7A):c.4567A>G(p.Lys1523Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SCN7A
NM_002976.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.19

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:

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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=0.058298796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN7A	NM_002976.4 linkuse as main transcript	c.4567A>G	p.Lys1523Glu	missense_variant	26/26	ENST00000643258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SCN7A	ENST00000643258.1 linkuse as main transcript	c.4567A>G	p.Lys1523Glu	missense_variant	26/26		NM_002976.4	P1
SCN7A	ENST00000441411.2 linkuse as main transcript	c.4567A>G	p.Lys1523Glu	missense_variant	25/25	1		P1
SCN7A	ENST00000424326.5 linkuse as main transcript	c.*2372A>G		3_prime_UTR_variant, NMD_transcript_variant	26/26	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460764

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726656

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000624

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.49

DEOGEN2

Benign

0.19

T;T;T;T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.80

.;T;.;.;.

M_CAP

Benign

0.0017

MetaRNN

Benign

0.058

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.4

N;N;N;N;N

MutationTaster

Benign

0.96

PrimateAI

Benign

0.27

PROVEAN

Benign

2.3

.;.;N;.;.

REVEL

Benign

0.052

Sift

Benign

1.0

.;.;T;.;.

Sift4G

Benign

1.0

T;T;T;.;.

Polyphen

0.0030

B;B;B;B;B

Vest4

0.076

MutPred

0.39

Loss of methylation at K1523 (P = 0.0089);Loss of methylation at K1523 (P = 0.0089);Loss of methylation at K1523 (P = 0.0089);Loss of methylation at K1523 (P = 0.0089);Loss of methylation at K1523 (P = 0.0089);

MVP

0.22

MPC

0.042

ClinPred

0.039

GERP RS

-4.2

Varity_R

0.047

gMVP

0.25

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over