rs80338784

Positions:

chr17-63959278-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000334.4(SCN4A):c.2006G>A(p.Arg669His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:2

Conservation

PhyloP100: 7.87

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]

SCN4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a transmembrane_region Helical; Name=S4 of repeat II (size 17) in uniprot entity SCN4A_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000334.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 17-63959278-C-T is Pathogenic according to our data. Variant chr17-63959278-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63959278-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN4A	NM_000334.4 linkuse as main transcript	c.2006G>A	p.Arg669His	missense_variant	12/24	ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3 linkuse as main transcript	c.2006G>A	p.Arg669His	missense_variant	12/24	1	NM_000334.4	ENSP00000396320	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000805

AC:

AN:

248518

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000930

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461012

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726742

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000146

Hom.:

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypokalemic periodic paralysis, type 2

Pathogenic:1Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2002	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Familial hyperkalemic periodic paralysis

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2021	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN4A function (PMID: 11102465, 11912116, 21881211, 25024265). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 5911). This missense change has been observed in individual(s) with hypokalemic periodic paralysis (PMID: 10599760, 18162704, 21841462). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs80338784, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 669 of the SCN4A protein (p.Arg669His). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 21, 2023

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to occur de novo in multiple individuals with clinical features of hypokalemic periodic paralysis. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11102465, 11912116, 21881211, 25024265) The variant is located in a region that is considered important for protein function and/or structure. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.029

Polyphen

0.99

Vest4

0.98

MutPred

0.96

Loss of MoRF binding (P = 0.0277);

MVP

0.98

MPC

0.99

ClinPred

1.0

GERP RS

4.9

Varity_R

0.91

gMVP

0.93

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over