chr17-63947922-C-G

Variant names:

• chr17-63947922-C-G
• rs766002690
• NM_000334.4:c.3286G>C

Variant summary

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

The NM_000334.4(SCN4A):​c.3286G>C​(p.Ala1096Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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]

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, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.3286G>C	p.Ala1096Pro	missense_variant	Exon 17 of 24	ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.3286G>C	p.Ala1096Pro	missense_variant	Exon 17 of 24	1	NM_000334.4	ENSP00000396320.1
SCN4A	ENST00000584310.1	n.*32G>C		downstream_gene_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 08, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.80
MutPred		0.69		Gain of loop (P = 0.069);
MVP		0.94
MPC		1.0
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.94
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs766002690; hg19: chr17-62025282;