rs41280102

Positions:

chr17-63951560-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000334.4(SCN4A):c.2717G>C(p.Ser906Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,613,998 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S906S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0099 ( 9 hom., cov: 32)

Exomes 𝑓: 0.014 ( 198 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 0.460

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004757881).

BP6

Variant 17-63951560-C-G is Benign according to our data. Variant chr17-63951560-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 21154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63951560-C-G is described in Lovd as [Benign]. Variant chr17-63951560-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00987 (1503/152296) while in subpopulation NFE AF= 0.015 (1017/68016). AF 95% confidence interval is 0.0142. There are 9 homozygotes in gnomad4. There are 681 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4 linkuse as main transcript	c.2717G>C	p.Ser906Thr	missense_variant	14/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3 linkuse as main transcript	c.2717G>C	p.Ser906Thr	missense_variant	14/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00988

AC:

1503

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00287

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.0300

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0149

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.00990

AC:

2467

AN:

249150

Hom.:

AF XY:

0.00990

AC XY:

1339

AN XY:

135194

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00869

Gnomad ASJ exome

AF:

0.0245

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00158

Gnomad NFE exome

AF:

0.0156

Gnomad OTH exome

AF:

0.0126

GnomAD4 exome

AF:

0.0143

AC:

20842

AN:

1461702

Hom.:

198

Cov.:

AF XY:

0.0142

AC XY:

10298

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.00224

Gnomad4 AMR exome

AF:

0.00915

Gnomad4 ASJ exome

AF:

0.0241

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00206

Gnomad4 NFE exome

AF:

0.0168

Gnomad4 OTH exome

AF:

0.0140

GnomAD4 genome

AF:

0.00987

AC:

1503

AN:

152296

Hom.:

Cov.:

AF XY:

0.00915

AC XY:

681

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00286

Gnomad4 AMR

AF:

0.0141

Gnomad4 ASJ

AF:

0.0300

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.0150

Gnomad4 OTH

AF:

0.0133

Alfa

AF:

0.0152

Hom.:

Bravo

AF:

0.0109

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0161

AC:

134

ExAC

AF:

0.00942

AC:

1139

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0186

EpiControl

AF:

0.0207

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 08, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2013	- -

Hyperkalemic periodic paralysis

Benign:2Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hypokalemic periodic paralysis, type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Paramyotonia congenita of Von Eulenburg

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 09, 2021

- -

Potassium-aggravated myotonia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Congenital myasthenic syndrome 16

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

8.5

DANN

Benign

0.83

DEOGEN2

Benign

0.31

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0048

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.0

REVEL

Benign

0.26

Sift

Benign

0.30

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.14

MVP

0.58

MPC

0.23

ClinPred

0.00098

GERP RS

4.0

Varity_R

0.16

gMVP

0.41

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