rs200770684

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000334.4(SCN4A):c.1100+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,613,216 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 8 hom. )

Consequence

SCN4A
NM_000334.4 splice_region, intron

Scores

Splicing: ADA: 0.00005459

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 0.764

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 17-63966474-C-T is Benign according to our data. Variant chr17-63966474-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255842.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=7}. Variant chr17-63966474-C-T is described in Lovd as [Benign]. Variant chr17-63966474-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00203 (309/152332) while in subpopulation NFE AF= 0.00243 (165/68024). AF 95% confidence interval is 0.00212. There are 0 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
SCN4A	NM_000334.4 linkuse as main transcript	c.1100+7G>A	splice_region_variant, intron_variant	ENST00000435607.3
LOC105371858	XR_001752969.2 linkuse as main transcript	n.346-31C>T	intron_variant, non_coding_transcript_variant
LOC105371858	XR_001752970.2 linkuse as main transcript	n.401-31C>T	intron_variant, non_coding_transcript_variant
LOC105371858	XR_934910.3 linkuse as main transcript	n.221-31C>T	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3 linkuse as main transcript	c.1100+7G>A		splice_region_variant, intron_variant		1	NM_000334.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00203

AC:

309

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00244

AC:

608

AN:

249140

Hom.:

AF XY:

0.00242

AC XY:

327

AN XY:

135190

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0110

Gnomad NFE exome

AF:

0.00305

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.00229

AC:

3346

AN:

1460884

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

1603

AN XY:

726792

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0119

Gnomad4 NFE exome

AF:

0.00230

Gnomad4 OTH exome

AF:

0.00239

GnomAD4 genome

AF:

0.00203

AC:

309

AN:

152332

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0104

Gnomad4 NFE

AF:

0.00243

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00184

Hom.:

Bravo

AF:

0.00107

EpiCase

AF:

0.00240

EpiControl

AF:

0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 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. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	SCN4A: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hyperkalemic periodic paralysis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	- -

Congenital myasthenic syndrome 16

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hypokalemic periodic paralysis, type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Paramyotonia congenita of Von Eulenburg

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 09, 2017

- -

Potassium-aggravated myotonia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

Cadd

Benign

6.5

Dann

Benign

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000055

dbscSNV1_RF

Benign

0.0020

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