17-63942988-T-C

Position:

• chr17-63942988-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000334.4(SCN4A):​c.4126A>G​(p.Asn1376Asp) variant causes a missense change. The variant allele was found at a frequency of 0.534 in 1,613,618 control chromosomes in the GnomAD database, including 233,301 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27022 hom., cov: 32)
  • Exomes 𝑓: 0.53 (206279 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.06

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a repeat IV (size 298) in uniprot entity SCN4A_HUMAN there are 26 pathogenic changes around while only 1 benign (96%) in NM_000334.4
• BP4: Computational evidence support a benign effect (MetaRNN=6.990708E-6).
• BP6: Variant 17-63942988-T-C is Benign according to our data. Variant chr17-63942988-T-C is described in ClinVar as [Benign]. Clinvar id is 130236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63942988-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.4126A>G	p.Asn1376Asp	missense_variant	23/24	ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.4126A>G	p.Asn1376Asp	missense_variant	23/24	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89335 AN: 151984 Hom.: 26984 Cov.: 32

Gnomad AFR AF: 0.733

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.599

GnomAD3 exomes AF: 0.523 AC: 131470 AN: 251184 Hom.: 35211 AF XY: 0.518 AC XY: 70269 AN XY: 135752

Gnomad AFR exome AF: 0.734

Gnomad AMR exome AF: 0.493

Gnomad ASJ exome AF: 0.596

Gnomad EAS exome AF: 0.511

Gnomad SAS exome AF: 0.394

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.546

GnomAD4 exome AF: 0.528 AC: 771980 AN: 1461516 Hom.: 206279 Cov.: 53 AF XY: 0.525 AC XY: 381860 AN XY: 727046

Gnomad4 AFR exome AF: 0.739

Gnomad4 AMR exome AF: 0.495

Gnomad4 ASJ exome AF: 0.603

Gnomad4 EAS exome AF: 0.501

Gnomad4 SAS exome AF: 0.395

Gnomad4 FIN exome AF: 0.510

Gnomad4 NFE exome AF: 0.532

Gnomad4 OTH exome AF: 0.539

GnomAD4 genome AF: 0.588 AC: 89426 AN: 152102 Hom.: 27022 Cov.: 32 AF XY: 0.581 AC XY: 43202 AN XY: 74354

Gnomad4 AFR AF: 0.733

Gnomad4 AMR AF: 0.518

Gnomad4 ASJ AF: 0.591

Gnomad4 EAS AF: 0.512

Gnomad4 SAS AF: 0.391

Gnomad4 FIN AF: 0.520

Gnomad4 NFE AF: 0.544

Gnomad4 OTH AF: 0.599

Alfa AF: 0.551 Hom.: 60005

Bravo AF: 0.597

TwinsUK AF: 0.536 AC: 1989

ALSPAC AF: 0.527 AC: 2031

ESP6500AA AF: 0.731 AC: 3221

ESP6500EA AF: 0.532 AC: 4574

ExAC AF: 0.523 AC: 63556

Asia WGS AF: 0.461 AC: 1608 AN: 3478

EpiCase AF: 0.556

EpiControl AF: 0.557

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 02, 2014	- -

Hyperkalemic periodic paralysis Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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. -

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. -

Congenital myasthenic syndrome 16 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
AlphaMissense	Benign	0.039
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.61
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0000070	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.8	N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	3.7	N
REVEL	Uncertain	0.33
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.052
MPC		0.29
ClinPred		0.0014	T
GERP RS		3.9
Varity_R		0.23
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2058194; hg19: chr17-62020348; COSMIC: COSV71125817; COSMIC: COSV71125817;