Variant 17-63948760-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000334.4(SCN4A):c.2995G>T(p.Val999Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V999M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.35

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4 linkuse as main transcript	c.2995G>T	p.Val999Leu	missense_variant	16/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3 linkuse as main transcript	c.2995G>T	p.Val999Leu	missense_variant	16/24	1	NM_000334.4	P1
SCN4A	ENST00000584310.1 linkuse as main transcript	n.318G>T		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000411

AC:

AN:

243126

Hom.:

AF XY:

0.00000757

AC XY:

AN XY:

132022

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452656

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721510

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial hyperkalemic periodic paralysis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Feb 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.094

MetaRNN

Uncertain

0.51

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.53

Sift

Uncertain

0.0020

Sift4G

Benign

0.32

Polyphen

0.85

Vest4

0.27

MutPred

0.65

Gain of helix (P = 0.0496);

MVP

0.81

MPC

0.60

ClinPred

0.83

GERP RS

4.2

Varity_R

0.49

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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