3-38925415-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001349253.2(SCN11A):c.712C>A(p.Arg238Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000276 in 1,447,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R238C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SCN11A NM_001349253.2 missense, splice_region
• Scores: Splicing: ADA: 0.0003254
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27536047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN11A	NM_001349253.2	c.712C>A	p.Arg238Ser	missense_variant, splice_region_variant	9/30	ENST00000302328.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN11A	ENST00000302328.9	c.712C>A	p.Arg238Ser	missense_variant, splice_region_variant	9/30	5	NM_001349253.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251028 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135640

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

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: 0.00000276 AC: 4 AN: 1447096 Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2 AN XY: 721058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

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

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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 submitter

clinical testing

Invitae

Sep 18, 2023

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. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 238 of the SCN11A protein (p.Arg238Ser). This variant is present in population databases (rs146942592, gnomAD 0.006%). 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 tolerated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	-0.83	N;N;N
MutationTaster	Benign	0.89	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.3	N;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.022	B;.;.
Vest4		0.28
MutPred		0.65		Loss of MoRF binding (P = 0.0424);Loss of MoRF binding (P = 0.0424);Loss of MoRF binding (P = 0.0424);
MVP		0.86
MPC		0.17
ClinPred		0.73	D
GERP RS		3.9
Varity_R		0.51
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00033
dbscSNV1_RF	Benign	0.050
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

Other links and lift over

dbSNP: rs146942592; hg19: chr3-38966906;