2-166405659-T-C

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.4970A>G(p.Asp1657Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0912 in 1,612,570 control chromosomes in the GnomAD database, including 7,450 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 0.076 (526 hom., cov: 32)
  • Exomes 𝑓: 0.093 (6924 hom.)
• Consequence: SCN7A NM_002976.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.130

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=0.0018896163).
• BP6: Variant 2-166405659-T-C is Benign according to our data. Variant chr2-166405659-T-C is described in ClinVar as [Benign]. Clinvar id is 3055990.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN7A	NM_002976.4	c.4970A>G	p.Asp1657Gly	missense_variant	26/26	ENST00000643258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN7A	ENST00000643258.1	c.4970A>G	p.Asp1657Gly	missense_variant	26/26		NM_002976.4	P1
SCN7A	ENST00000441411.2	c.4970A>G	p.Asp1657Gly	missense_variant	25/25	1		P1
SCN7A	ENST00000424326.5	c.*2775A>G		3_prime_UTR_variant, NMD_transcript_variant	26/26	1

Frequencies

GnomAD3 genomes AF: 0.0757 AC: 11508 AN: 152036 Hom.: 526 Cov.: 32

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0505

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0800

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0964

Gnomad OTH AF: 0.0923

GnomAD3 exomes AF: 0.0850 AC: 21085 AN: 248152 Hom.: 1092 AF XY: 0.0887 AC XY: 11943 AN XY: 134620

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.0453

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.0150

Gnomad SAS exome AF: 0.117

Gnomad FIN exome AF: 0.0860

Gnomad NFE exome AF: 0.0969

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.0929 AC: 135616 AN: 1460416 Hom.: 6924 Cov.: 33 AF XY: 0.0942 AC XY: 68455 AN XY: 726502

Gnomad4 AFR exome AF: 0.0427

Gnomad4 AMR exome AF: 0.0486

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.0149

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.0875

Gnomad4 NFE exome AF: 0.0948

Gnomad4 OTH exome AF: 0.101

GnomAD4 genome AF: 0.0756 AC: 11507 AN: 152154 Hom.: 526 Cov.: 32 AF XY: 0.0732 AC XY: 5449 AN XY: 74390

Gnomad4 AFR AF: 0.0447

Gnomad4 AMR AF: 0.0505

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.0800

Gnomad4 NFE AF: 0.0964

Gnomad4 OTH AF: 0.0952

Alfa AF: 0.0942 Hom.: 1068

Bravo AF: 0.0716

TwinsUK AF: 0.103 AC: 381

ALSPAC AF: 0.0942 AC: 363

ESP6500AA AF: 0.0426 AC: 158

ESP6500EA AF: 0.0985 AC: 807

ExAC AF: 0.0858 AC: 10360

Asia WGS AF: 0.0860 AC: 300 AN: 3478

EpiCase AF: 0.101

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

Nov 26, 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	0.073
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	9.9
Dann	Benign	0.66
DEOGEN2	Benign	0.19	T;T;T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	0.0019	T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.26	N;N;N;N;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
Sift4G	Benign	0.44	T;T;T;.;.
Polyphen		0.0010	B;B;B;B;B
Vest4		0.046
MPC		0.041
ClinPred		0.00021	T
GERP RS		0.94
Varity_R		0.040
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

Other links and lift over

dbSNP: rs35344714; hg19: chr2-167262169; COSMIC: COSV69273640;