17-63939367-C-CACACATATAT

Variant names:

• chr17-63939367-C-CACACATATAT
• rs112489358
• NM_000334.4:c.*1394_*1403dupATATATGTGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000334.4(SCN4A):​c.*1394_*1403dupATATATGTGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15906 hom., cov: 0)
  • Exomes 𝑓: 0.13 (2 hom.)
• Consequence: SCN4A NM_000334.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.130
• Publications: 7 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet
• paramyotonia congenita of Von Eulenburg

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

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

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

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

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -16 ACMG points.

• BP6: Variant 17-63939367-C-CACACATATAT is Benign according to our data. Variant chr17-63939367-C-CACACATATAT is described in ClinVar as Benign. ClinVar VariationId is 324479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000334.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4A	NM_000334.4	MANE Select	c.*1394_*1403dupATATATGTGT		3_prime_UTR	Exon 24 of 24	NP_000325.4	P35499

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4A	ENST00000435607.3	TSL:1 MANE Select	c.*1394_*1403dupATATATGTGT		3_prime_UTR	Exon 24 of 24	ENSP00000396320.1	P35499

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65261 AN: 151246 Hom.: 15902 Cov.: 0

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.456

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.474

GnomAD4 exome AF: 0.132 AC: 10 AN: 76 Hom.: 2 Cov.: 0 AF XY: 0.113 AC XY: 7 AN XY: 62

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.250 AC: 1 AN: 4

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.148 AC: 8 AN: 54

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.431 AC: 65289 AN: 151362 Hom.: 15906 Cov.: 0 AF XY: 0.429 AC XY: 31701 AN XY: 73896

African (AFR) AF: 0.192 AC: 7932 AN: 41388

American (AMR) AF: 0.440 AC: 6683 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 1926 AN: 3458

East Asian (EAS) AF: 0.456 AC: 2316 AN: 5084

South Asian (SAS) AF: 0.385 AC: 1845 AN: 4790

European-Finnish (FIN) AF: 0.523 AC: 5460 AN: 10434

Middle Eastern (MID) AF: 0.552 AC: 160 AN: 290

European-Non Finnish (NFE) AF: 0.553 AC: 37431 AN: 67724

Other (OTH) AF: 0.476 AC: 999 AN: 2098

Alfa AF: 0.294 Hom.: 684

Asia WGS AF: 0.400 AC: 1395 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital Myasthenic Syndrome, Recessive (1)
-	-	1	Hyperkalemic periodic paralysis (1)
-	-	1	Hypokalemic periodic paralysis (1)
-	-	1	not provided (1)
-	-	1	Paramyotonia congenita of Von Eulenburg (1)
-	-	1	Potassium-aggravated myotonia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs112489358; hg19: chr17-62016727; COSMIC: COSV104437284;