2-166406011-C-A

Position:

• chr2-166406011-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002976.4(SCN7A):​c.4618G>T​(p.Asp1540Tyr) 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 1,460,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.66

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN7A	NM_002976.4	c.4618G>T	p.Asp1540Tyr	missense_variant	26/26	ENST00000643258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN7A	ENST00000643258.1	c.4618G>T	p.Asp1540Tyr	missense_variant	26/26		NM_002976.4	P1
SCN7A	ENST00000441411.2	c.4618G>T	p.Asp1540Tyr	missense_variant	25/25	1		P1
SCN7A	ENST00000424326.5	c.*2423G>T		3_prime_UTR_variant, NMD_transcript_variant	26/26	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000202 AC: 5 AN: 248024 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134556

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460914 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 726732

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

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.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000331 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;D;D;D;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;D;.;.;.
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.1	M;M;M;M;M
MutationTaster	Benign	0.91	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.5	.;.;D;.;.
REVEL	Benign	0.16
Sift	Pathogenic	0.0	.;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.47
MutPred		0.45		Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);
MVP		0.45
MPC		0.27
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.86
gMVP		0.70

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: rs767621934; hg19: chr2-167262521; COSMIC: COSV69270404;