rs115304957

chr17-63972214-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000334.4(SCN4A):c.404T>C(p.Met135Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000768 in 1,613,522 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M135L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (6 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.46

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011093706).
• BP6: Variant 17-63972214-A-G is Benign according to our data. Variant chr17-63972214-A-G is described in ClinVar as [Benign]. Clinvar id is 477420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63972214-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00437 (665/152270) while in subpopulation AFR AF= 0.015 (625/41556). AF 95% confidence interval is 0.0141. There are 5 homozygotes in gnomad4. There are 317 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.404T>C	p.Met135Thr	missense_variant	3/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.404T>C	p.Met135Thr	missense_variant	3/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes AF: 0.00436 AC: 663 AN: 152152 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

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: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00111 AC: 275 AN: 248290 Hom.: 5 AF XY: 0.000846 AC XY: 114 AN XY: 134704

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.000990

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000393 AC: 574 AN: 1461252 Hom.: 6 Cov.: 31 AF XY: 0.000354 AC XY: 257 AN XY: 726882

Gnomad4 AFR exome AF: 0.0140

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.00437 AC: 665 AN: 152270 Hom.: 5 Cov.: 32 AF XY: 0.00426 AC XY: 317 AN XY: 74444

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00215 Hom.: 2

Bravo AF: 0.00513

ESP6500AA AF: 0.0114 AC: 49

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00142 AC: 172

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 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 12, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	24
Dann	Benign	0.93
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	-0.040
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.53
Sift	Benign	0.12	T
Sift4G	Benign	0.16	T
Polyphen		0.027	B
Vest4		0.53
MVP		0.87
MPC		0.29
ClinPred		0.060	T
GERP RS		3.6
Varity_R		0.34
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs115304957; hg19: chr17-62049574;