17-63968234-G-C

Position:

• chr17-63968234-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1 PM2 PP3_Moderate

The NM_000334.4(SCN4A):​c.825C>G​(p.Asn275Lys) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.51

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 8 ACMG points.

• PS1: Transcript NM_000334.4 (SCN4A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.825C>G	p.Asn275Lys	missense_variant	6/24	ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.825C>G	p.Asn275Lys	missense_variant	6/24	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.2	L
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.57
Sift	Benign	0.11	T
Sift4G	Benign	0.29	T
Polyphen		0.77	P
Vest4		0.82
MutPred		0.63		Gain of ubiquitination at N275 (P = 0.0494);
MVP		0.84
MPC		0.37
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.71
gMVP		0.95

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: rs199789700; hg19: chr17-62045594;