rs542836462

Positions:

• chr17-63971269-AG-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000334.4(SCN4A):​c.612-17del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 403,824 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: SCN4A NM_000334.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.281

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 -16 ACMG points.

• BP6: Variant 17-63971269-AG-A is Benign according to our data. Variant chr17-63971269-AG-A is described in ClinVar as [Benign]. Clinvar id is 255860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00984 (698/70942) while in subpopulation AFR AF= 0.0346 (677/19590). AF 95% confidence interval is 0.0324. There are 8 homozygotes in gnomad4. There are 316 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.612-17del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.612-17del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000334.4	P1

Frequencies

GnomAD3 genomes AF: 0.00983 AC: 697 AN: 70908 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

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: 0.00

Gnomad OTH AF: 0.00610

GnomAD3 exomes AF: 0.00145 AC: 151 AN: 104450 Hom.: 0 AF XY: 0.00106 AC XY: 61 AN XY: 57318

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000756

Gnomad NFE exome AF: 0.0000452

Gnomad OTH exome AF: 0.000743

GnomAD4 exome AF: 0.00145 AC: 482 AN: 332882 Hom.: 3 Cov.: 20 AF XY: 0.00110 AC XY: 193 AN XY: 176226

Gnomad4 AFR exome AF: 0.0399

Gnomad4 AMR exome AF: 0.00135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000178

Gnomad4 SAS exome AF: 0.0000271

Gnomad4 FIN exome AF: 0.0000393

Gnomad4 NFE exome AF: 0.0000574

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.00984 AC: 698 AN: 70942 Hom.: 8 Cov.: 32 AF XY: 0.00900 AC XY: 316 AN XY: 35102

Gnomad4 AFR AF: 0.0346

Gnomad4 AMR AF: 0.00230

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00604

Alfa AF: 0.00283 Hom.: 0

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 21, 2016	- -

Hyperkalemic periodic paralysis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs542836462; hg19: chr17-62048629;