Genetic Variant SCN4A:c.612-94G>A (chr17-63971347-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000334.4(SCN4A):c.612-94G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 747,310 control chromosomes in the GnomAD database, including 49,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 8267 hom., cov: 30)

Exomes 𝑓: 0.36 ( 41065 hom. )

Consequence

SCN4A
NM_000334.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.38

Variant links:

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]

SCN4A links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 17-63971347-C-T is Benign according to our data. Variant chr17-63971347-C-T is described in ClinVar as [Benign]. Clinvar id is 1265211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4A	NM_000334.4 link	c.612-94G>A		intron_variant	Intron 4 of 23	ENST00000435607.3	NP_000325.4	P35499

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3 link	c.612-94G>A		intron_variant	Intron 4 of 23	1	NM_000334.4	ENSP00000396320.1		P35499

Frequencies

GnomAD3 genomes

AF:

0.310

AC:

47003

AN:

151626

Hom.:

8259

Cov.:

show subpopulations

Gnomad AFR

AF:

0.149

Gnomad AMI

AF:

0.425

Gnomad AMR

AF:

0.270

Gnomad ASJ

AF:

0.404

Gnomad EAS

AF:

0.308

Gnomad SAS

AF:

0.264

Gnomad FIN

AF:

0.363

Gnomad MID

AF:

0.364

Gnomad NFE

AF:

0.405

Gnomad OTH

AF:

0.318

GnomAD4 exome

AF:

0.362

AC:

215373

AN:

595564

Hom.:

41065

AF XY:

0.360

AC XY:

113868

AN XY:

316676

show subpopulations

Gnomad4 AFR exome

AF:

0.146

Gnomad4 AMR exome

AF:

0.239

Gnomad4 ASJ exome

AF:

0.394

Gnomad4 EAS exome

AF:

0.329

Gnomad4 SAS exome

AF:

0.281

Gnomad4 FIN exome

AF:

0.365

Gnomad4 NFE exome

AF:

0.398

Gnomad4 OTH exome

AF:

0.357

GnomAD4 genome

AF:

0.310

AC:

47015

AN:

151746

Hom.:

8267

Cov.:

AF XY:

0.305

AC XY:

22643

AN XY:

74122

show subpopulations

Gnomad4 AFR

AF:

0.149

Gnomad4 AMR

AF:

0.270

Gnomad4 ASJ

AF:

0.404

Gnomad4 EAS

AF:

0.309

Gnomad4 SAS

AF:

0.264

Gnomad4 FIN

AF:

0.363

Gnomad4 NFE

AF:

0.405

Gnomad4 OTH

AF:

0.321

Alfa

AF:

0.373

Hom.:

12367

Bravo

AF:

0.297

Asia WGS

AF:

0.271

AC:

943

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 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

-0.83

CADD

Benign

1.2

DANN

Benign

0.55

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over