17-63971855-G-C

Position:

• chr17-63971855-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000334.4(SCN4A):​c.483-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,525,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 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 0.00049 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: SCN4A NM_000334.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004237
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: -2.91

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.483-5C>G		splice_region_variant, intron_variant		ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.483-5C>G		splice_region_variant, intron_variant		1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes AF: 0.000494 AC: 59 AN: 119330 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000165

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000740

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000186

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000165 AC: 40 AN: 241898 Hom.: 0 AF XY: 0.000182 AC XY: 24 AN XY: 131510

Gnomad AFR exome AF: 0.000544

Gnomad AMR exome AF: 0.0000608

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000233

Gnomad SAS exome AF: 0.000271

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000145

Gnomad OTH exome AF: 0.000345

GnomAD4 exome AF: 0.000223 AC: 314 AN: 1406338 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 159 AN XY: 697612

Gnomad4 AFR exome AF: 0.000745

Gnomad4 AMR exome AF: 0.000144

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000238

Gnomad4 SAS exome AF: 0.000424

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000204

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000494 AC: 59 AN: 119452 Hom.: 0 Cov.: 30 AF XY: 0.000577 AC XY: 34 AN XY: 58946

Gnomad4 AFR AF: 0.00127

Gnomad4 AMR AF: 0.000165

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000742

Gnomad4 SAS AF: 0.00107

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000186

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000325

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2023	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Hyperkalemic periodic paralysis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2023

- -

SCN4A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 10, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.056
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.058
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 32

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs191547933; hg19: chr17-62049215;