2-166406062-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002976.4(SCN7A):ā€‹c.4567A>Gā€‹(p.Lys1523Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

SCN7A
NM_002976.4 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.19
Variant links:
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.058298796).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN7ANM_002976.4 linkuse as main transcriptc.4567A>G p.Lys1523Glu missense_variant 26/26 ENST00000643258.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN7AENST00000643258.1 linkuse as main transcriptc.4567A>G p.Lys1523Glu missense_variant 26/26 NM_002976.4 P1
SCN7AENST00000441411.2 linkuse as main transcriptc.4567A>G p.Lys1523Glu missense_variant 25/251 P1
SCN7AENST00000424326.5 linkuse as main transcriptc.*2372A>G 3_prime_UTR_variant, NMD_transcript_variant 26/261

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1460764
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
726656
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000624
Hom.:
0
Bravo
AF:
0.0000113
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
13
DANN
Benign
0.49
DEOGEN2
Benign
0.19
T;T;T;T;T
Eigen
Benign
-0.97
Eigen_PC
Benign
-0.81
FATHMM_MKL
Benign
0.47
N
LIST_S2
Benign
0.80
.;T;.;.;.
M_CAP
Benign
0.0017
T
MetaRNN
Benign
0.058
T;T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
-1.4
N;N;N;N;N
MutationTaster
Benign
0.96
N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
2.3
.;.;N;.;.
REVEL
Benign
0.052
Sift
Benign
1.0
.;.;T;.;.
Sift4G
Benign
1.0
T;T;T;.;.
Polyphen
0.0030
B;B;B;B;B
Vest4
0.076
MutPred
0.39
Loss of methylation at K1523 (P = 0.0089);Loss of methylation at K1523 (P = 0.0089);Loss of methylation at K1523 (P = 0.0089);Loss of methylation at K1523 (P = 0.0089);Loss of methylation at K1523 (P = 0.0089);
MVP
0.22
MPC
0.042
ClinPred
0.039
T
GERP RS
-4.2
Varity_R
0.047
gMVP
0.25

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: rs1701064149; hg19: chr2-167262572; API