rs6738031

chr2-166423412-C-Achr2-166423412-C-Gchr2-166423412-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.75 (43536 hom., cov: 30)
  • Exomes 𝑓: 0.69 (343827 hom.)
• Consequence: SCN7A NM_002976.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.02

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 3059687.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN7A	NM_002976.4	c.2874G>T	p.Met958Ile	missense_variant	19/26	ENST00000643258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN7A	ENST00000643258.1	c.2874G>T	p.Met958Ile	missense_variant	19/26		NM_002976.4	P1
SCN7A	ENST00000441411.2	c.2874G>T	p.Met958Ile	missense_variant	18/25	1		P1
SCN7A	ENST00000424326.5	c.*679G>T		3_prime_UTR_variant, NMD_transcript_variant	19/26	1

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113479 AN: 151630 Hom.: 43476 Cov.: 30

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

GnomAD3 exomes AF: 0.696 AC: 144203 AN: 207238 Hom.: 50161 AF XY: 0.691 AC XY: 77579 AN XY: 112280

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 SAS exome AF: 0.707

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.: 32 AF XY: 0.693 AC XY: 489923 AN XY: 706642

Gnomad4 AFR exome AF: 0.938

Gnomad4 AMR exome AF: 0.688

Gnomad4 ASJ exome AF: 0.672

Gnomad4 EAS exome AF: 0.688

Gnomad4 SAS exome AF: 0.713

Gnomad4 FIN exome AF: 0.666

Gnomad4 NFE exome AF: 0.687

Gnomad4 OTH exome AF: 0.708

GnomAD4 genome AF: 0.749 AC: 113597 AN: 151750 Hom.: 43536 Cov.: 30 AF XY: 0.746 AC XY: 55276 AN XY: 74140

Gnomad4 AFR AF: 0.930

Gnomad4 AMR AF: 0.693

Gnomad4 ASJ AF: 0.655

Gnomad4 EAS AF: 0.669

Gnomad4 SAS AF: 0.705

Gnomad4 FIN AF: 0.674

Gnomad4 NFE AF: 0.675

Gnomad4 OTH AF: 0.747

Alfa AF: 0.680 Hom.: 74671

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SCN7A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

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	0.083
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	0.019
Dann	Benign	0.55
DEOGEN2	Uncertain	0.46	T;T;T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.019	N
MetaRNN	Benign	7.5e-7	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.8	N;N;N;N;N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.50	T
Sift4G	Benign	1.0	T;T;T;.;.
Polyphen		0.0	B;B;B;B;B
Vest4		0.090
MutPred		0.52		Loss of phosphorylation at Y957 (P = 0.0825);Loss of phosphorylation at Y957 (P = 0.0825);Loss of phosphorylation at Y957 (P = 0.0825);Loss of phosphorylation at Y957 (P = 0.0825);Loss of phosphorylation at Y957 (P = 0.0825);
MPC		0.036
ClinPred		0.00030	T
GERP RS		-1.5
Varity_R		0.065
gMVP		0.096

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

LitVar

Other links and lift over

dbSNP: rs6738031; hg19: chr2-167279922; COSMIC: COSV69268701;