chr3-38846750-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001349253.2(SCN11A):ā€‹c.5320T>Cā€‹(p.Cys1774Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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‘“: 0.0000027 ( 0 hom. )

Consequence

SCN11A
NM_001349253.2 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.998
Variant links:
Genes affected
SCN11A (HGNC:10583): (sodium voltage-gated channel alpha subunit 11) 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, and is highly expressed in nociceptive neurons of dorsal root ganglia and trigeminal ganglia. It mediates brain-derived neurotrophic factor-evoked membrane depolarization and is a major effector of peripheral inflammatory pain hypersensitivity. Mutations in this gene have been associated with hereditary sensory and autonomic neuropathy type VII and familial episodic pain syndrome-3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2017]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18168256).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN11ANM_001349253.2 linkuse as main transcriptc.5320T>C p.Cys1774Arg missense_variant 30/30 ENST00000302328.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN11AENST00000302328.9 linkuse as main transcriptc.5320T>C p.Cys1774Arg missense_variant 30/305 NM_001349253.2 A2Q9UI33-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461872
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
727232
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:
0.00000180
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000370
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 30, 2023This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1774 of the SCN11A protein (p.Cys1774Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN11A-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Benign
21
DANN
Benign
0.96
DEOGEN2
Benign
0.088
T;.
Eigen
Benign
-0.46
Eigen_PC
Benign
-0.32
FATHMM_MKL
Benign
0.19
N
LIST_S2
Benign
0.63
T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.18
T;T
MetaSVM
Uncertain
0.039
D
MutationAssessor
Benign
1.9
M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-2.2
N;N
REVEL
Uncertain
0.38
Sift
Uncertain
0.0020
D;D
Sift4G
Benign
0.72
T;T
Polyphen
0.011
B;.
Vest4
0.23
MutPred
0.52
Loss of sheet (P = 0.0181);.;
MVP
0.86
MPC
0.60
ClinPred
0.55
D
GERP RS
4.9
Varity_R
0.77
gMVP
0.41

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: rs2064670816; hg19: chr3-38888241; API