chr2-166406011-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002976.4(SCN7A):​c.4618G>T​(p.Asp1540Tyr) 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 1,460,914 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 (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SCN7A
NM_002976.4 missense

Scores

7
6
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.66
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN7ANM_002976.4 linkuse as main transcriptc.4618G>T p.Asp1540Tyr missense_variant 26/26 ENST00000643258.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN7AENST00000643258.1 linkuse as main transcriptc.4618G>T p.Asp1540Tyr missense_variant 26/26 NM_002976.4 P1
SCN7AENST00000441411.2 linkuse as main transcriptc.4618G>T p.Asp1540Tyr missense_variant 25/251 P1
SCN7AENST00000424326.5 linkuse as main transcriptc.*2423G>T 3_prime_UTR_variant, NMD_transcript_variant 26/261

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000202
AC:
5
AN:
248024
Hom.:
0
AF XY:
0.0000223
AC XY:
3
AN XY:
134556
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000146
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1460914
Hom.:
0
Cov.:
33
AF XY:
0.00000550
AC XY:
4
AN XY:
726732
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
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:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ExAC
AF:
0.0000331
AC:
4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.34
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.72
D;D;D;D;D
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
.;D;.;.;.
M_CAP
Benign
0.020
T
MetaRNN
Pathogenic
0.77
D;D;D;D;D
MetaSVM
Benign
-0.86
T
MutationAssessor
Pathogenic
3.1
M;M;M;M;M
MutationTaster
Benign
0.91
D
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-6.5
.;.;D;.;.
REVEL
Benign
0.16
Sift
Pathogenic
0.0
.;.;D;.;.
Sift4G
Pathogenic
0.0
D;D;D;.;.
Polyphen
1.0
D;D;D;D;D
Vest4
0.47
MutPred
0.45
Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);
MVP
0.45
MPC
0.27
ClinPred
0.96
D
GERP RS
4.7
Varity_R
0.86
gMVP
0.70

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: rs767621934; hg19: chr2-167262521; COSMIC: COSV69270404; API