17-63964718-T-C

Variant names:

• chr17-63964718-T-C
• rs2877373
• NM_000334.4:c.1243-41A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000334.4(SCN4A):​c.1243-41A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.886 in 1,513,008 control chromosomes in the GnomAD database, including 598,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (51411 hom., cov: 32)
  • Exomes 𝑓: 0.89 (547390 hom.)
• Consequence: SCN4A NM_000334.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.254

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]

LOC105371858 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-63964718-T-C is Benign according to our data. Variant chr17-63964718-T-C is described in ClinVar as [Benign]. Clinvar id is 255843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63964718-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.1243-41A>G		intron_variant	Intron 8 of 23	ENST00000435607.3	NP_000325.4
LOC105371858	XR_001752969.2	n.345+68T>C		intron_variant	Intron 4 of 4
LOC105371858	XR_001752970.2	n.400+68T>C		intron_variant	Intron 4 of 4
LOC105371858	XR_934910.3	n.220+68T>C		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.1243-41A>G		intron_variant	Intron 8 of 23	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122715 AN: 152048 Hom.: 51395 Cov.: 32

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.890

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.935

Gnomad FIN AF: 0.872

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.901

Gnomad OTH AF: 0.831

GnomAD3 exomes AF: 0.893 AC: 158714 AN: 177688 Hom.: 71624 AF XY: 0.900 AC XY: 85383 AN XY: 94902

Gnomad AFR exome AF: 0.541

Gnomad AMR exome AF: 0.934

Gnomad ASJ exome AF: 0.912

Gnomad EAS exome AF: 0.978

Gnomad SAS exome AF: 0.932

Gnomad FIN exome AF: 0.878

Gnomad NFE exome AF: 0.899

Gnomad OTH exome AF: 0.899

GnomAD4 exome AF: 0.895 AC: 1217720 AN: 1360842 Hom.: 547390 Cov.: 21 AF XY: 0.897 AC XY: 605875 AN XY: 675328

Gnomad4 AFR exome AF: 0.533

Gnomad4 AMR exome AF: 0.931

Gnomad4 ASJ exome AF: 0.913

Gnomad4 EAS exome AF: 0.964

Gnomad4 SAS exome AF: 0.930

Gnomad4 FIN exome AF: 0.876

Gnomad4 NFE exome AF: 0.900

Gnomad4 OTH exome AF: 0.888

GnomAD4 genome AF: 0.807 AC: 122769 AN: 152166 Hom.: 51411 Cov.: 32 AF XY: 0.810 AC XY: 60291 AN XY: 74388

Gnomad4 AFR AF: 0.555

Gnomad4 AMR AF: 0.890

Gnomad4 ASJ AF: 0.913

Gnomad4 EAS AF: 0.973

Gnomad4 SAS AF: 0.935

Gnomad4 FIN AF: 0.872

Gnomad4 NFE AF: 0.901

Gnomad4 OTH AF: 0.833

Alfa AF: 0.847 Hom.: 7834

Bravo AF: 0.797

Asia WGS AF: 0.920 AC: 3198 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.3
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2877373; hg19: chr17-62042078;