rs191547933

Positions:

• chr17-63971855-G-A
• chr17-63971855-G-C
• chr17-63971855-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000334.4(SCN4A):​c.483-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000511 in 1,525,790 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00028 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: SCN4A NM_000334.4 splice_region, intron
• Scores: Splicing: ADA: 0.000008072
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-63971855-G-A is Benign according to our data. Variant chr17-63971855-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 706149.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000268 AC: 32 AN: 119330 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000890

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000826

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000372

Gnomad OTH AF: 0.000663

GnomAD3 exomes AF: 0.0000827 AC: 20 AN: 241898 Hom.: 0 AF XY: 0.0000684 AC XY: 9 AN XY: 131510

Gnomad AFR exome AF: 0.000476

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000677

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.0000814

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000313 AC: 44 AN: 1406338 Hom.: 0 Cov.: 33 AF XY: 0.0000258 AC XY: 18 AN XY: 697612

Gnomad4 AFR exome AF: 0.000435

Gnomad4 AMR exome AF: 0.0000481

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000530

Gnomad4 SAS exome AF: 0.0000794

Gnomad4 FIN exome AF: 0.0000197

Gnomad4 NFE exome AF: 0.0000139

Gnomad4 OTH exome AF: 0.0000695

GnomAD4 genome AF: 0.000285 AC: 34 AN: 119452 Hom.: 0 Cov.: 30 AF XY: 0.000271 AC XY: 16 AN XY: 58946

Gnomad4 AFR AF: 0.000950

Gnomad4 AMR AF: 0.0000825

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000372

Gnomad4 OTH AF: 0.000653

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 02, 2024

Variant summary: SCN4A c.483-5C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.3e-05 in 241898 control chromosomes (gnomAD). To our knowledge, no occurrence of c.483-5C>T in individuals affected with Acetazolamide-Responsive Myotonia and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 20, 2022

- -

Hyperkalemic periodic paralysis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0080
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000081
dbscSNV1_RF	Benign	0.012
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

Other links and lift over

dbSNP: rs191547933; hg19: chr17-62049215;