chr17-63963719-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000334.4(SCN4A):​c.1559C>T​(p.Pro520Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000306 in 1,600,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P520R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.86
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 Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.18642136).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN4ANM_000334.4 linkuse as main transcriptc.1559C>T p.Pro520Leu missense_variant 10/24 ENST00000435607.3
LOC105371858XR_001752969.2 linkuse as main transcriptn.119-365G>A intron_variant, non_coding_transcript_variant
LOC105371858XR_001752970.2 linkuse as main transcriptn.174-365G>A intron_variant, non_coding_transcript_variant
LOC105371858XR_934910.3 linkuse as main transcriptn.118+405G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN4AENST00000435607.3 linkuse as main transcriptc.1559C>T p.Pro520Leu missense_variant 10/241 NM_000334.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152186
Hom.:
0
Cov.:
34
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000167
AC:
4
AN:
239054
Hom.:
0
AF XY:
0.0000153
AC XY:
2
AN XY:
130320
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000578
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000276
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000324
AC:
47
AN:
1448812
Hom.:
0
Cov.:
34
AF XY:
0.0000306
AC XY:
22
AN XY:
719482
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000256
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000398
Gnomad4 OTH exome
AF:
0.0000334
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152186
Hom.:
0
Cov.:
34
AF XY:
0.0000135
AC XY:
1
AN XY:
74340
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hyperkalemic periodic paralysis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 31, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN4A protein function. ClinVar contains an entry for this variant (Variation ID: 663353). This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 520 of the SCN4A protein (p.Pro520Leu). -
Congenital myasthenic syndrome 16 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsDec 13, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.070
CADD
Benign
21
DANN
Benign
0.93
DEOGEN2
Benign
0.28
T
Eigen
Benign
-0.53
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.46
N
LIST_S2
Benign
0.59
T
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.19
T
MetaSVM
Uncertain
0.13
D
MutationAssessor
Benign
0.83
L
MutationTaster
Benign
0.89
D;D
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-1.3
N
REVEL
Uncertain
0.37
Sift
Benign
0.35
T
Sift4G
Uncertain
0.059
T
Polyphen
0.20
B
Vest4
0.26
MutPred
0.21
Loss of glycosylation at P520 (P = 0.0357);
MVP
0.79
MPC
0.26
ClinPred
0.090
T
GERP RS
2.9
Varity_R
0.053
gMVP
0.39

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: rs753391449; hg19: chr17-62041079; API