2-166406313-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_002976.4(SCN7A):āc.4316T>Cā(p.Met1439Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,106 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 Uncertain significance (ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 32)
Exomes š: 0.000034 ( 0 hom. )
Consequence
SCN7A
NM_002976.4 missense
NM_002976.4 missense
Scores
9
5
1
Clinical Significance
Conservation
PhyloP100: 9.25
Genes affected
SCN7A (HGNC:10594): (sodium voltage-gated channel alpha subunit 7) This gene encodes one of the many voltage-gated sodium channel proteins. For proper functioning of neurons and muscles during action potentials, voltage-gated sodium channels direct sodium ion diffusion for membrane depolarization. This sodium channel protein has some atypical characteristics; the similarity between the human and mouse proteins is lower compared to other orthologous sodium channel pairs. Also, the S4 segments, which sense voltage changes, have fewer positive charged residues that in other sodium channels; domain 4 has fewer arginine and lysine residues compared to other sodium channel proteins. Several alternatively spliced transcript variants exist, but the full-length natures of all of them remain unknown. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.931
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN7A | NM_002976.4 | c.4316T>C | p.Met1439Thr | missense_variant | 26/26 | ENST00000643258.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN7A | ENST00000643258.1 | c.4316T>C | p.Met1439Thr | missense_variant | 26/26 | NM_002976.4 | P1 | ||
SCN7A | ENST00000441411.2 | c.4316T>C | p.Met1439Thr | missense_variant | 25/25 | 1 | P1 | ||
SCN7A | ENST00000424326.5 | c.*2121T>C | 3_prime_UTR_variant, NMD_transcript_variant | 26/26 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 151998Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000483 AC: 12AN: 248408Hom.: 0 AF XY: 0.0000594 AC XY: 8AN XY: 134732
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GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461108Hom.: 0 Cov.: 33 AF XY: 0.0000330 AC XY: 24AN XY: 726854
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 151998Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74228
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 22, 2023 | The c.4316T>C (p.M1439T) alteration is located in exon 25 (coding exon 24) of the SCN7A gene. This alteration results from a T to C substitution at nucleotide position 4316, causing the methionine (M) at amino acid position 1439 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;M;M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D;D;D;.;.
Polyphen
D;D;D;D;D
Vest4
MutPred
Loss of stability (P = 0.0694);Loss of stability (P = 0.0694);Loss of stability (P = 0.0694);Loss of stability (P = 0.0694);Loss of stability (P = 0.0694);
MVP
MPC
0.21
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at