17-63951632-G-T

Variant names:

• chr17-63951632-G-T
• rs111858905
• NM_000334.4:c.2645C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000334.4(SCN4A):​c.2645C>A​(p.Pro882Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000674 in 1,612,446 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P882L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (3 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.988
• Publications: 1 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 -19 ACMG points.

• 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=0.0061502457).
• BP6: Variant 17-63951632-G-T is Benign according to our data. Variant chr17-63951632-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 324529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0035 (533/152214) while in subpopulation AFR AF = 0.0122 (506/41532). AF 95% confidence interval is 0.0113. There are 6 homozygotes in GnomAd4. There are 246 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.2645C>A	p.Pro882Gln	missense	Exon 14 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.2645C>A	p.Pro882Gln	missense	Exon 14 of 24	ENSP00000396320.1	P35499

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 531 AN: 152096 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.000912 AC: 223 AN: 244584 AF XY: 0.000655

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000382

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000723

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000379 AC: 553 AN: 1460232 Hom.: 3 Cov.: 32 AF XY: 0.000328 AC XY: 238 AN XY: 726312

African (AFR) AF: 0.0131 AC: 438 AN: 33456

American (AMR) AF: 0.000427 AC: 19 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111230

Other (OTH) AF: 0.000945 AC: 57 AN: 60314

GnomAD4 genome AF: 0.00350 AC: 533 AN: 152214 Hom.: 6 Cov.: 32 AF XY: 0.00331 AC XY: 246 AN XY: 74430

African (AFR) AF: 0.0122 AC: 506 AN: 41532

American (AMR) AF: 0.00124 AC: 19 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67980

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00140 Hom.: 2

Bravo AF: 0.00401

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00952 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000935 AC: 113

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hyperkalemic periodic paralysis (2)
-	-	1	Congenital myasthenic syndrome 16 (1)
-	-	1	Hypokalemic periodic paralysis, type 2 (1)
-	-	1	not specified (1)
-	-	1	Paramyotonia congenita of Von Eulenburg (1)
-	-	1	Potassium-aggravated myotonia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.99
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.12
Sift	Benign	0.43	T
Sift4G	Benign	0.32	T
Polyphen		0.049	B
Vest4		0.28
MVP		0.53
MPC		0.24
ClinPred		0.0029	T
GERP RS		1.0
Varity_R		0.031
gMVP		0.47
Mutation Taster		=91/9	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: rs111858905; hg19: chr17-62028992;