rs75168694

Variant names:

• chr17-63963848-G-A
• rs75168694
• NM_000334.4:c.1453-23C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000334.4(SCN4A):​c.1453-23C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,580,630 control chromosomes in the GnomAD database, including 604 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.020 (64 hom., cov: 33)
  • Exomes 𝑓: 0.023 (540 hom.)
• Consequence: SCN4A NM_000334.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0100

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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-63963848-G-A is Benign according to our data. Variant chr17-63963848-G-A is described in ClinVar as [Benign]. Clinvar id is 255844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63963848-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0201 (3066/152356) while in subpopulation NFE AF= 0.0318 (2162/68038). AF 95% confidence interval is 0.0307. There are 64 homozygotes in gnomad4. There are 1511 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 64 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4A	NM_000334.4	c.1453-23C>T		intron_variant	Intron 9 of 23	ENST00000435607.3	NP_000325.4
LOC105371858	XR_001752969.2	n.119-236G>A		intron_variant	Intron 2 of 4
LOC105371858	XR_001752970.2	n.174-236G>A		intron_variant	Intron 2 of 4
LOC105371858	XR_934910.3	n.118+534G>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3	c.1453-23C>T		intron_variant	Intron 9 of 23	1	NM_000334.4	ENSP00000396320.1

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3065 AN: 152238 Hom.: 64 Cov.: 33

Gnomad AFR AF: 0.00354

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0510

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0318

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0208 AC: 4139 AN: 198914 Hom.: 64 AF XY: 0.0206 AC XY: 2217 AN XY: 107858

Gnomad AFR exome AF: 0.00300

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00198

Gnomad FIN exome AF: 0.0581

Gnomad NFE exome AF: 0.0304

Gnomad OTH exome AF: 0.0180

GnomAD4 exome AF: 0.0235 AC: 33500 AN: 1428274 Hom.: 540 Cov.: 34 AF XY: 0.0233 AC XY: 16505 AN XY: 707620

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00392

Gnomad4 ASJ exome AF: 0.0244

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00192

Gnomad4 FIN exome AF: 0.0548

Gnomad4 NFE exome AF: 0.0262

Gnomad4 OTH exome AF: 0.0185

GnomAD4 genome AF: 0.0201 AC: 3066 AN: 152356 Hom.: 64 Cov.: 33 AF XY: 0.0203 AC XY: 1511 AN XY: 74504

Gnomad4 AFR AF: 0.00353

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0510

Gnomad4 NFE AF: 0.0318

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0346 Hom.: 37

Bravo AF: 0.0145

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 17, 2018

GeneDx

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	-0.88
CADD	Benign	1.5
DANN	Benign	0.24
BranchPoint Hunter		0.0

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: rs75168694; hg19: chr17-62041208;