17-63964639-G-T

Position:

• chr17-63964639-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000334.4(SCN4A):​c.1281C>A​(p.Phe427Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65

Genes affected

SCN4A (HGNC:10591): (sodium voltage-gated channel alpha subunit 4) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders. [provided by RefSeq, Jul 2008]

LOC105371858 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.1281C>A	p.Phe427Leu	missense_variant	9/24	ENST00000435607.3	NP_000325.4
LOC105371858	XR_001752969.2	n.334G>T		non_coding_transcript_exon_variant	4/5
LOC105371858	XR_001752970.2	n.389G>T		non_coding_transcript_exon_variant	4/5
LOC105371858	XR_934910.3	n.209G>T		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.1281C>A	p.Phe427Leu	missense_variant	9/24	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459652 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725948

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: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	11
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Benign	0.061
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.22	N
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.73		Gain of catalytic residue at F427 (P = 0.0183);
MVP		0.93
MPC		0.98
ClinPred		1.0	D
GERP RS		-4.3
Varity_R		0.94
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs369445518; hg19: chr17-62041999;