chr17-63964587-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_000334.4(SCN4A):​c.1333G>T​(p.Val445Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,388 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V445M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SCN4A
NM_000334.4 missense

Scores

14
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U: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 Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-63964587-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.94
PP5
Variant 17-63964587-C-A is Pathogenic according to our data. Variant chr17-63964587-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 373945.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}. Variant chr17-63964587-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN4ANM_000334.4 linkc.1333G>T p.Val445Leu missense_variant Exon 9 of 24 ENST00000435607.3 NP_000325.4 P35499
LOC105371858XR_001752969.2 linkn.282C>A non_coding_transcript_exon_variant Exon 4 of 5
LOC105371858XR_001752970.2 linkn.337C>A non_coding_transcript_exon_variant Exon 4 of 5
LOC105371858XR_934910.3 linkn.157C>A non_coding_transcript_exon_variant Exon 3 of 4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN4AENST00000435607.3 linkc.1333G>T p.Val445Leu missense_variant Exon 9 of 24 1 NM_000334.4 ENSP00000396320.1 P35499

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461388
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726978
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Batten-Turner congenital myopathy Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJun 23, 2016- -
Hyperkalemic periodic paralysis Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2016This variant was classified as: Likely pathogenic. -
Pain;C0030196:Limb pain;C0151786:Muscle weakness;C1847584:Distal sensory impairment;C4022169:EMG: myotonic discharges Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2017- -
Muscle weakness;C0700153:Myotonia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJun 11, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.43
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
D
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D
M_CAP
Pathogenic
0.59
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.2
M
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-2.4
N
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.016
D
Polyphen
1.0
D
Vest4
0.85
MutPred
0.76
Loss of helix (P = 0.1299);
MVP
0.96
MPC
0.90
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.79
gMVP
0.89

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: rs121908552; hg19: chr17-62041947; API