rs115304957

Positions:

chr17-63972214-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000435607.3(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
ENST00000435607.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN4A	NM_000334.4 linkuse as main transcript	c.404T>C	p.Met135Thr	missense_variant	3/24	ENST00000435607.3	NP_000325.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN4A	ENST00000435607.3 linkuse as main transcript	c.404T>C	p.Met135Thr	missense_variant	3/24	1	NM_000334.4	ENSP00000396320	P1

Frequencies

GnomAD3 genomes

AF:

0.00436

AC:

663

AN:

152152

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000846

AC XY:

114

AN XY:

134704

show subpopulations

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.:

Cov.:

AF XY:

0.000354

AC XY:

257

AN XY:

726882

show subpopulations

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.:

Cov.:

AF XY:

0.00426

AC XY:

317

AN XY:

74444

show subpopulations

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.:

Bravo

AF:

0.00513

ESP6500AA

AF:

0.0114

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00142

AC:

172

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 15, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

Familial hyperkalemic periodic paralysis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Benign

0.93

DEOGEN2

Pathogenic

0.85

Eigen

Benign

-0.040

Eigen_PC

Benign

0.066

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.53

Sift

Benign

0.12

Sift4G

Benign

0.16

Polyphen

0.027

Vest4

0.53

MVP

0.87

MPC

0.29

ClinPred

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over