rs62070884

Variant names:

• chr17-63957197-C-T
• rs62070884
• NM_000334.4:c.2341G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000334.4(SCN4A):​c.2341G>A​(p.Val781Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 1,590,850 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (70 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21 O:1
• Conservation: PhyloP100: 7.91
• Publications: 21 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 -17 ACMG points.

• PM1: In a repeat II (size 272) in uniprot entity SCN4A_HUMAN there are 27 pathogenic changes around while only 3 benign (90%) in NM_000334.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 97 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 1.5606 (below the threshold of 3.09). Trascript score misZ: 2.2224 (below the threshold of 3.09). GenCC associations: The gene is linked to SCN4A-related myopathy, autosomal recessive, hyperkalemic periodic paralysis, paramyotonia congenita of Von Eulenburg, congenital myasthenic syndrome 16, acetazolamide-responsive myotonia, myotonia permanens, hypokalemic periodic paralysis, type 2, potassium-aggravated myotonia, congenital myopathy 22A, classic, congenital myopathy, myotonia fluctuans, postsynaptic congenital myasthenic syndrome, hypokalemic periodic paralysis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.015130967).
• BP6: Variant 17-63957197-C-T is Benign according to our data. Variant chr17-63957197-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00872 (1328/152304) while in subpopulation AMR AF = 0.031 (474/15286). AF 95% confidence interval is 0.0287. There are 7 homozygotes in GnomAd4. There are 745 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

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.2341G>A	p.Val781Ile	missense	Exon 13 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.2341G>A	p.Val781Ile	missense	Exon 13 of 24	ENSP00000396320.1	P35499

Frequencies

GnomAD3 genomes AF: 0.00874 AC: 1330 AN: 152186 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0311

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00979

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00804

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.0106 AC: 2533 AN: 239510 AF XY: 0.00942

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.0304

Gnomad ASJ exome AF: 0.00310

Gnomad EAS exome AF: 0.0189

Gnomad FIN exome AF: 0.00842

Gnomad NFE exome AF: 0.00764

Gnomad OTH exome AF: 0.00667

GnomAD4 exome AF: 0.00761 AC: 10941 AN: 1438546 Hom.: 70 Cov.: 31 AF XY: 0.00735 AC XY: 5233 AN XY: 711532

African (AFR) AF: 0.00117 AC: 39 AN: 33226

American (AMR) AF: 0.0307 AC: 1355 AN: 44080

Ashkenazi Jewish (ASJ) AF: 0.00351 AC: 87 AN: 24766

East Asian (EAS) AF: 0.0239 AC: 940 AN: 39340

South Asian (SAS) AF: 0.00150 AC: 125 AN: 83268

European-Finnish (FIN) AF: 0.00851 AC: 448 AN: 52640

Middle Eastern (MID) AF: 0.00141 AC: 8 AN: 5672

European-Non Finnish (NFE) AF: 0.00695 AC: 7618 AN: 1096230

Other (OTH) AF: 0.00541 AC: 321 AN: 59324

GnomAD4 genome AF: 0.00872 AC: 1328 AN: 152304 Hom.: 7 Cov.: 32 AF XY: 0.0100 AC XY: 745 AN XY: 74474

African (AFR) AF: 0.00185 AC: 77 AN: 41570

American (AMR) AF: 0.0310 AC: 474 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.0187 AC: 97 AN: 5178

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00979 AC: 104 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00804 AC: 547 AN: 68028

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00791 Hom.: 14

Bravo AF: 0.00920

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00900 AC: 1093

Asia WGS AF: 0.00635 AC: 23 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	2	Hyperkalemic periodic paralysis (3)
-	-	1	Congenital myasthenic syndrome 16 (1)
-	-	1	Hypokalemic periodic paralysis, type 2 (1)
-	-	1	Joubert syndrome 17 (1)
-	-	1	Paramyotonia congenita of Von Eulenburg (1)
-	-	1	Paramyotonia congenita of Von Eulenburg;C0238357:Hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C3714580:Hypokalemic periodic paralysis, type 1 (1)
-	-	1	Potassium-aggravated myotonia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.93	N
REVEL	Pathogenic	0.73
Sift	Benign	0.051	T
Sift4G	Benign	0.39	T
Polyphen		0.89	P
Vest4		0.79
MPC		0.65
ClinPred		0.019	T
GERP RS		3.9
Varity_R		0.35
gMVP		0.63
Mutation Taster		=88/12	polymorphism

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: rs62070884; hg19: chr17-62034557; COSMIC: COSV107528634; COSMIC: COSV107528634;