rs543502873

Variant summary

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

The NM_000334.4(SCN4A):ā€‹c.448A>Cā€‹(p.Met150Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,588 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000085 ( 0 hom., cov: 32)
Exomes š‘“: 0.00011 ( 2 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

4
15

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.525
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.016021132).
BP6
Variant 17-63972170-T-G is Benign according to our data. Variant chr17-63972170-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 477423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000854 (13/152242) while in subpopulation SAS AF= 0.00269 (13/4826). AF 95% confidence interval is 0.00159. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN4ANM_000334.4 linkuse as main transcriptc.448A>C p.Met150Leu missense_variant 3/24 ENST00000435607.3 NP_000325.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN4AENST00000435607.3 linkuse as main transcriptc.448A>C p.Met150Leu missense_variant 3/241 NM_000334.4 ENSP00000396320 P1

Frequencies

GnomAD3 genomes
AF:
0.0000855
AC:
13
AN:
152124
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00269
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000245
AC:
61
AN:
248580
Hom.:
1
AF XY:
0.000378
AC XY:
51
AN XY:
134858
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00194
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000331
GnomAD4 exome
AF:
0.000115
AC:
168
AN:
1461346
Hom.:
2
Cov.:
31
AF XY:
0.000176
AC XY:
128
AN XY:
726934
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00187
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152242
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00269
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.000239
AC:
29
Asia WGS
AF:
0.00231
AC:
8
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial hyperkalemic periodic paralysis Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 26, 2022- -
Paramyotonia congenita of Von Eulenburg;C0238357:Familial hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 07, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.091
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
20
DANN
Benign
0.88
DEOGEN2
Uncertain
0.68
D
Eigen
Benign
-0.42
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.59
D
LIST_S2
Benign
0.82
T
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.016
T
MetaSVM
Uncertain
0.23
D
MutationAssessor
Benign
0.97
L
MutationTaster
Benign
0.99
D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-1.4
N
REVEL
Uncertain
0.33
Sift
Benign
0.32
T
Sift4G
Benign
0.64
T
Polyphen
0.0
B
Vest4
0.32
MutPred
0.45
Loss of disorder (P = 0.0829);
MVP
0.71
MPC
0.24
ClinPred
0.012
T
GERP RS
3.6
Varity_R
0.28
gMVP
0.63

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: rs543502873; hg19: chr17-62049530; API