17-63964587-C-T

Position:

chr17-63964587-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000334.4(SCN4A):c.1333G>A(p.Val445Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. V445L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.90

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:

LOC105371858 (HGNC:):

LOC105371858 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 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 chr17-63964587-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448262.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=3, Uncertain_significance=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 17-63964587-C-T is Pathogenic according to our data. Variant chr17-63964587-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63964587-C-T is described in Lovd as [Pathogenic]. Variant chr17-63964587-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SCN4A	NM_000334.4 linkuse as main transcript	c.1333G>A	p.Val445Met	missense_variant	9/24	ENST00000435607.3
LOC105371858	XR_001752969.2 linkuse as main transcript	n.282C>T		non_coding_transcript_exon_variant	4/5
LOC105371858	XR_001752970.2 linkuse as main transcript	n.337C>T		non_coding_transcript_exon_variant	4/5
LOC105371858	XR_934910.3 linkuse as main transcript	n.157C>T		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3 linkuse as main transcript	c.1333G>A	p.Val445Met	missense_variant	9/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248570

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134982

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461388

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2021	Published functional studies demonstrate a damaging effect as this variant results in a defect in sodium channel gating (Wang et al., 1999); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19840739, 25839108, 10218481, 17334961, 25724373, 9392583, 27415035, 28325641, 18337100, 31567646, 9929487, 32849172, 32670189, 33263785, 32660787, 22653516) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 06, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant causes defects in the inactivation properties of the mutant sodium channel (PMID 10218481). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 09, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 26, 2021	PP1_Strong, PS3, PP3, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	SCN4A: PM2, PM5, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 13, 2023	- -

SCN4A-related non-dystrophic myotonia

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences

Apr 06, 2022

- -

Familial hyperkalemic periodic paralysis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 445 of the SCN4A protein (p.Val445Met). This variant is present in population databases (rs121908552, gnomAD 0.003%). This missense change has been observed in individuals with myotonia congenita and is associated with marked phenotypic variability (PMID: 9392583, 17334961, 19840739, 22653516, 25724373, 25839108). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5910). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN4A protein function. Experimental studies have shown that this missense change affects SCN4A function (PMID: 10218481, 11744749). For these reasons, this variant has been classified as Pathogenic. -

Potassium-aggravated myotonia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2009

- -

Paramyotonia congenita of Von Eulenburg;C0238357:Familial hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C3714580:Hypokalemic periodic paralysis, type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.5

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.95

MutPred

0.92

Gain of helix (P = 0.2059);

MVP

0.96

MPC

0.91

ClinPred

1.0

GERP RS

4.9

Varity_R

0.69

gMVP

0.87

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