2-166423412-C-G

Position:

• chr2-166423412-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002976.4(SCN7A):​c.2874G>C​(p.Met958Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN7A NM_002976.4 missense
• Clinical Significance: Not reported in ClinVar
• 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]

SCN7A (HGNC:):

ACMG classification

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=0.06148559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN7A	NM_002976.4	c.2874G>C	p.Met958Ile	missense_variant	19/26	ENST00000643258.1	NP_002967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN7A	ENST00000643258.1	c.2874G>C	p.Met958Ile	missense_variant	19/26		NM_002976.4	ENSP00000496114.1
SCN7A	ENST00000441411.2	c.2874G>C	p.Met958Ile	missense_variant	18/25	1		ENSP00000403846.2
SCN7A	ENST00000424326.5	n.*679G>C		non_coding_transcript_exon_variant	19/26	1		ENSP00000396600.1
SCN7A	ENST00000424326.5	n.*679G>C		3_prime_UTR_variant	19/26	1		ENSP00000396600.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1425854 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 707928

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.018
DANN	Benign	0.45
DEOGEN2	Uncertain	0.46	T;T;T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.57	.;T;.;.;.
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.061	T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	-1.8	N;N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	2.6	.;.;N;.;.
REVEL	Uncertain	0.34
Sift	Benign	1.0	.;.;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);
MVP		0.55
MPC		0.036
ClinPred		0.061	T
GERP RS		-1.5
Varity_R		0.065
gMVP		0.096

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: rs6738031; hg19: chr2-167279922;