rs201379704

chr17-63972688-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000334.4(SCN4A):c.154C>T(p.Arg52Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000474 in 1,613,644 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R52Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.49

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007462889).
• BP6: Variant 17-63972688-G-A is Benign according to our data. Variant chr17-63972688-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 477399.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00244 (371/152258) while in subpopulation AFR AF= 0.00814 (338/41546). AF 95% confidence interval is 0.00742. There are 6 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.154C>T	p.Arg52Trp	missense_variant	1/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.154C>T	p.Arg52Trp	missense_variant	1/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 371 AN: 152140 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00816

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.000725 AC: 180 AN: 248422 Hom.: 4 AF XY: 0.000594 AC XY: 80 AN XY: 134776

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000270 AC: 394 AN: 1461386 Hom.: 2 Cov.: 32 AF XY: 0.000239 AC XY: 174 AN XY: 726942

Gnomad4 AFR exome AF: 0.00917

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.00244 AC: 371 AN: 152258 Hom.: 6 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74436

Gnomad4 AFR AF: 0.00814

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.000417 Hom.: 2

Bravo AF: 0.00290

ESP6500AA AF: 0.00745 AC: 31

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000818 AC: 99

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

Possible pathogenicity based on finding it once in our laboratory in trans with another variant [p.R3T] in a 1-year-old female with congenital hypotonia, proximal weakness, mixed developmental disorder, congenital myasthenia gravis, GERD, failure to thrive. Variant has also been seen in others in combination with additional variants (phase unknown) but without features of this syndrome. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hyperkalemic periodic paralysis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0075	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.89	P
Vest4		0.30
MVP		0.85
MPC		0.31
ClinPred		0.042	T
GERP RS		-0.71
Varity_R		0.10
gMVP		0.44

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

Other links and lift over

dbSNP: rs201379704; hg19: chr17-62050048;