rs867587467

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP5_Moderate

The NM_000334.4(SCN4A):​c.692C>T​(p.Thr231Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000782 in 1,407,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

13
5
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 10.0
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a transmembrane_region Helical; Name=S4 of repeat I (size 16) in uniprot entity SCN4A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000334.4
PP5
Variant 17-63971173-G-A is Pathogenic according to our data. Variant chr17-63971173-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521304.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN4ANM_000334.4 linkuse as main transcriptc.692C>T p.Thr231Met missense_variant 5/24 ENST00000435607.3 NP_000325.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN4AENST00000435607.3 linkuse as main transcriptc.692C>T p.Thr231Met missense_variant 5/241 NM_000334.4 ENSP00000396320 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000117
AC:
2
AN:
170542
Hom.:
0
AF XY:
0.0000110
AC XY:
1
AN XY:
90752
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000812
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000144
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000782
AC:
11
AN:
1407066
Hom.:
0
Cov.:
33
AF XY:
0.00000720
AC XY:
5
AN XY:
694910
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000218
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000277
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 21, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.96
D
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.41
D
MetaRNN
Uncertain
0.68
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-3.3
D
REVEL
Pathogenic
0.79
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.52
MutPred
0.57
Gain of ubiquitination at K228 (P = 0.0704);
MVP
0.97
MPC
0.92
ClinPred
0.98
D
GERP RS
4.2
Varity_R
0.58
gMVP
0.83

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

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

Other links and lift over

dbSNP: rs867587467; hg19: chr17-62048533; COSMIC: COSV71128482; COSMIC: COSV71128482; API