NM_000334.4:c.612-94G>A

Variant names:

• chr17-63971347-C-T
• rs2302237
• NM_000334.4:c.612-94G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.38
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• hyperkalemic periodic paralysis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• paramyotonia congenita of Von Eulenburg

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• SCN4A-related myopathy, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• hypokalemic periodic paralysis, type 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• potassium-aggravated myotonia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 16

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital myopathy 22A, classic

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• acetazolamide-responsive myotonia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypokalemic periodic paralysis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myotonia fluctuans

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myotonia permanens

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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	c.612-94G>A		intron_variant	Intron 4 of 23	ENST00000435607.3	NP_000325.4

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47003 AN: 151626 Hom.: 8259 Cov.: 30

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

African (AFR) AF: 0.146 AC: 2418 AN: 16580

American (AMR) AF: 0.239 AC: 8114 AN: 33976

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 7582 AN: 19252

East Asian (EAS) AF: 0.329 AC: 10478 AN: 31848

South Asian (SAS) AF: 0.281 AC: 17271 AN: 61508

European-Finnish (FIN) AF: 0.365 AC: 13017 AN: 35666

Middle Eastern (MID) AF: 0.357 AC: 890 AN: 2492

European-Non Finnish (NFE) AF: 0.398 AC: 144397 AN: 362852

Other (OTH) AF: 0.357 AC: 11206 AN: 31390

GnomAD4 genome AF: 0.310 AC: 47015 AN: 151746 Hom.: 8267 Cov.: 30 AF XY: 0.305 AC XY: 22643 AN XY: 74122

African (AFR) AF: 0.149 AC: 6175 AN: 41456

American (AMR) AF: 0.270 AC: 4125 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1397 AN: 3462

East Asian (EAS) AF: 0.309 AC: 1586 AN: 5136

South Asian (SAS) AF: 0.264 AC: 1270 AN: 4810

European-Finnish (FIN) AF: 0.363 AC: 3821 AN: 10532

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.405 AC: 27470 AN: 67778

Other (OTH) AF: 0.321 AC: 677 AN: 2106

Alfa AF: 0.370 Hom.: 14822

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

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.55
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2302237; hg19: chr17-62048707;