rs121908560

chr17-63944694-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000334.4(SCN4A):c.3891C>A(p.Asn1297Lys) variant causes a missense change. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1297S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.28

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000334.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-63944695-T-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 17-63944694-G-T is Pathogenic according to our data. Variant chr17-63944694-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 5922.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.3891C>A	p.Asn1297Lys	missense_variant	21/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.3891C>A	p.Asn1297Lys	missense_variant	21/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Paramyotonia congenita of Von Eulenburg Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

Jun 22, 2023

- -

Paramyotonia congenita/hyperkalemic periodic paralysis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.88		Gain of methylation at N1297 (P = 6e-04);
MVP		0.93
MPC		0.97
ClinPred		1.0	D
GERP RS		2.6
Varity_R		0.95
gMVP		0.86

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: rs121908560; hg19: chr17-62022054;