2-166405843-C-G

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.4786G>C(p.Val1596Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0961 in 1,612,964 control chromosomes in the GnomAD database, including 8,123 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.081 (597 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7526 hom.)
• Consequence: SCN7A NM_002976.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.134

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=0.001709193).
• BP6: Variant 2-166405843-C-G is Benign according to our data. Variant chr2-166405843-C-G is described in ClinVar as [Benign]. Clinvar id is 3057148.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN7A	NM_002976.4	c.4786G>C	p.Val1596Leu	missense_variant	26/26	ENST00000643258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN7A	ENST00000643258.1	c.4786G>C	p.Val1596Leu	missense_variant	26/26		NM_002976.4	P1
SCN7A	ENST00000441411.2	c.4786G>C	p.Val1596Leu	missense_variant	25/25	1		P1
SCN7A	ENST00000424326.5	c.*2591G>C		3_prime_UTR_variant, NMD_transcript_variant	26/26	1

Frequencies

GnomAD3 genomes AF: 0.0813 AC: 12348 AN: 151938 Hom.: 597 Cov.: 32

Gnomad AFR AF: 0.0469

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0505

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0858

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0969

Gnomad OTH AF: 0.0964

GnomAD3 exomes AF: 0.0958 AC: 23746 AN: 247866 Hom.: 1313 AF XY: 0.0996 AC XY: 13396 AN XY: 134436

Gnomad AFR exome AF: 0.0439

Gnomad AMR exome AF: 0.0454

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.130

Gnomad SAS exome AF: 0.131

Gnomad FIN exome AF: 0.0903

Gnomad NFE exome AF: 0.0974

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.0976 AC: 142611 AN: 1460908 Hom.: 7526 Cov.: 33 AF XY: 0.0993 AC XY: 72166 AN XY: 726738

Gnomad4 AFR exome AF: 0.0441

Gnomad4 AMR exome AF: 0.0488

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.138

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.0912

Gnomad4 NFE exome AF: 0.0951

Gnomad4 OTH exome AF: 0.107

GnomAD4 genome AF: 0.0812 AC: 12345 AN: 152056 Hom.: 597 Cov.: 32 AF XY: 0.0798 AC XY: 5932 AN XY: 74318

Gnomad4 AFR AF: 0.0468

Gnomad4 AMR AF: 0.0504

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.0858

Gnomad4 NFE AF: 0.0969

Gnomad4 OTH AF: 0.0991

Alfa AF: 0.102 Hom.: 615

Bravo AF: 0.0773

TwinsUK AF: 0.103 AC: 383

ALSPAC AF: 0.0944 AC: 364

ESP6500AA AF: 0.0444 AC: 167

ESP6500EA AF: 0.0976 AC: 803

ExAC AF: 0.0965 AC: 11661

Asia WGS AF: 0.123 AC: 428 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.100

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 21, 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	0.082
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	11
Dann	Benign	0.73
DEOGEN2	Benign	0.20	T;T;T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.023	N
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-1.9	N;N;N;N;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.27	T;T;T;.;.
Polyphen		0.0	B;B;B;B;B
Vest4		0.015
MPC		0.033
ClinPred		0.00049	T
GERP RS		1.6
Varity_R		0.029
gMVP		0.17

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

Other links and lift over

dbSNP: rs3791251; hg19: chr2-167262353; COSMIC: COSV69271760;