17-63959270-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The ENST00000435607.3(SCN4A):​c.2014C>A​(p.Arg672Ser) 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. R672C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SCN4A
ENST00000435607.3 missense

Scores

13
5
1

Clinical Significance

Pathogenic criteria provided, single submitter P:3O:2

Conservation

PhyloP100: 4.52
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000435607.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-63959270-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 21151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 17-63959270-G-T is Pathogenic according to our data. Variant chr17-63959270-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 5916.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-63959270-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN4ANM_000334.4 linkuse as main transcriptc.2014C>A p.Arg672Ser missense_variant 12/24 ENST00000435607.3 NP_000325.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN4AENST00000435607.3 linkuse as main transcriptc.2014C>A p.Arg672Ser missense_variant 12/241 NM_000334.4 ENSP00000396320 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3Other:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypokalemic periodic paralysis, type 2 Pathogenic:1Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 23, 2004- -
not provided, no classification providedliterature onlyGeneReviews-- -
Familial hyperkalemic periodic paralysis Pathogenic:1Other:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 20, 2023This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 672 of the SCN4A protein (p.Arg672Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypokalemic periodic paralysis (HOKPP) (PMID: 11558801, 11591859, 15557532, 15645704, 26252573). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5916). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN4A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 11558801, 18824591). This variant disrupts the p.Arg672 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10944223, 11912116, 15482957, 17330043, 18824591, 19225109, 20660662, 22253645, 23019082, 25024265, 26252573). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification providedliterature onlyGeneReviews-- -
Hypokalemic periodic paralysis Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingMolecular Genetics Laboratory, BC Children's and BC Women's HospitalsNov 29, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.93
D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.0
H
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-5.7
D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
0.0010
B
Vest4
0.97
MutPred
0.97
Loss of MoRF binding (P = 0.0277);
MVP
0.94
MPC
0.86
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.98
gMVP
0.98

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80338785; hg19: chr17-62036630; API