17-63943846-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_000334.4(SCN4A):ā€‹c.3917G>Cā€‹(p.Gly1306Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,601,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1306E) has been classified as Pathogenic.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

10
7
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 7.90
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1
In a topological_domain Cytoplasmic (size 62) in uniprot entity SCN4A_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000334.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-63943846-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.901
PP5
Variant 17-63943846-C-G is Pathogenic according to our data. Variant chr17-63943846-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63943846-C-G is described in Lovd as [Pathogenic]. Variant chr17-63943846-C-G is described in Lovd as [Likely_pathogenic]. Variant chr17-63943846-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN4ANM_000334.4 linkc.3917G>C p.Gly1306Ala missense_variant Exon 22 of 24 ENST00000435607.3 NP_000325.4 P35499

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN4AENST00000435607.3 linkc.3917G>C p.Gly1306Ala missense_variant Exon 22 of 24 1 NM_000334.4 ENSP00000396320.1 P35499

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249512
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135334
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000483
AC:
7
AN:
1449642
Hom.:
0
Cov.:
27
AF XY:
0.00000139
AC XY:
1
AN XY:
721982
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000636
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000147
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000825
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:6
Jun 01, 2022
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 25, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies indicate that this variant impairs fast inactivation as compared to wild type (Lerche et al., 1993); Predicted to be within the intracellular loop between the third and fourth homologous domain; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32369273, 25525159, 7980103, 8308722, 31307605, 29774303, 28877545, 32849172, 32670189, 26080010, 31544778, 26885337, 32660787, 32528171) -

Sep 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SCN4A: PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -

Nov 24, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2014
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 14, 2023
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in individuals with myotonia and segregates with disease in multiple families. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 7473241, 8740371, 16392038). -

Hyperkalemic periodic paralysis Pathogenic:1
Jan 13, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1306 of the SCN4A protein (p.Gly1306Ala). This variant is present in population databases (rs80338792, gnomAD 0.0009%). This missense change has been observed in individual(s) with myotonia fluctuans (PMID: 7980103, 8308722, 26080010, 26885337). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5908). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN4A protein function. Experimental studies have shown that this missense change affects SCN4A function (PMID: 7473241, 16392038). This variant disrupts the p.Gly1306 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8308722, 16832098, 17823953, 20713951). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Myotonia fluctuans Pathogenic:1
Nov 01, 1994
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Potassium-aggravated myotonia Pathogenic:1
Jun 22, 2022
MGZ Medical Genetics Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Paramyotonia congenita of Von Eulenburg;C0238357:Hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia Other:1
-
GenomeConnect - Invitae Patient Insights Network
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 12-18-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.79
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
H
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-4.5
D
REVEL
Pathogenic
0.87
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.012
D
Polyphen
0.54
P
Vest4
0.56
MutPred
0.79
Gain of catalytic residue at G1306 (P = 0.0465);
MVP
0.85
MPC
0.46
ClinPred
0.98
D
GERP RS
3.4
Varity_R
0.70
gMVP
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs80338792; hg19: chr17-62021206; API