chr2-166406062-T-C

Position:

• chr2-166406062-T-C

Variant summary

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

The NM_002976.4(SCN7A):​c.4567A>G​(p.Lys1523Glu) 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 1,460,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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: 2.19

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 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=0.058298796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN7A	NM_002976.4	c.4567A>G	p.Lys1523Glu	missense_variant	26/26	ENST00000643258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN7A	ENST00000643258.1	c.4567A>G	p.Lys1523Glu	missense_variant	26/26		NM_002976.4	P1
SCN7A	ENST00000441411.2	c.4567A>G	p.Lys1523Glu	missense_variant	25/25	1		P1
SCN7A	ENST00000424326.5	c.*2372A>G		3_prime_UTR_variant, NMD_transcript_variant	26/26	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460764 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726656

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.49
DEOGEN2	Benign	0.19	T;T;T;T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.80	.;T;.;.;.
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.058	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.4	N;N;N;N;N
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	2.3	.;.;N;.;.
REVEL	Benign	0.052
Sift	Benign	1.0	.;.;T;.;.
Sift4G	Benign	1.0	T;T;T;.;.
Polyphen		0.0030	B;B;B;B;B
Vest4		0.076
MutPred		0.39		Loss of methylation at K1523 (P = 0.0089);Loss of methylation at K1523 (P = 0.0089);Loss of methylation at K1523 (P = 0.0089);Loss of methylation at K1523 (P = 0.0089);Loss of methylation at K1523 (P = 0.0089);
MVP		0.22
MPC		0.042
ClinPred		0.039	T
GERP RS		-4.2
Varity_R		0.047
gMVP		0.25

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: rs1701064149; hg19: chr2-167262572;