chr3-38871584-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001349253.2(SCN11A):​c.3620G>T​(p.Cys1207Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,788 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 (★). Synonymous variant affecting the same amino acid position (i.e. C1207C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SCN11A
NM_001349253.2 missense

Scores

13
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.69
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN11ANM_001349253.2 linkuse as main transcriptc.3620G>T p.Cys1207Phe missense_variant 25/30 ENST00000302328.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN11AENST00000302328.9 linkuse as main transcriptc.3620G>T p.Cys1207Phe missense_variant 25/305 NM_001349253.2 A2Q9UI33-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460788
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726692
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

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 testingInvitaeMar 16, 2018In 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SCN11A-related disease. This sequence change replaces cysteine with phenylalanine at codon 1207 of the SCN11A protein (p.Cys1207Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.96
D;.;.
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Pathogenic
0.49
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.6
H;.;H
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-10
D;D;D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.013
D;D;D
Sift4G
Uncertain
0.0070
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.86
MutPred
0.88
Loss of methylation at K1206 (P = 0.0514);.;Loss of methylation at K1206 (P = 0.0514);
MVP
0.98
MPC
0.78
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.92
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs904970580; hg19: chr3-38913075; COSMIC: COSV56572349; API