rs80356474

Positions:

• chr2-166277281-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001365536.1(SCN9A):​c.2576T>C​(p.Ile859Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 9.13

Genes affected

SCN9A (HGNC:10597): (sodium voltage-gated channel alpha subunit 9) This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 2-166277281-A-G is Pathogenic according to our data. Variant chr2-166277281-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 6350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166277281-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2576T>C	p.Ile859Thr	missense_variant	16/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2576T>C	p.Ile859Thr	missense_variant	16/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2576T>C	p.Ile859Thr	missense_variant	16/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2543T>C	p.Ile848Thr	missense_variant	16/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2543T>C	p.Ile848Thr	missense_variant	16/27			ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 17, 2021	- -

Primary erythromelalgia Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 22, 2004	- -

SCN9A-related peripheral neuropathies associated with increased pain Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 12, 2019

The SCN9A c.2543T>C (p.Ile848Thr) variant is a missense variant and has been reported in at least seven studies, in which it is found in a heterozygous state in a total of 10 individuals with inherited erythromelalgia (Yang et al. 2004; Drenth et al. 2005; Drenth et al. 2008; Natkunarajah et al. 2009; Zhang et al. 2014; Namer et al. 2015; McDonnell et al. 2016). The age of onset was reported at three to five years in individuals carrying the p.Ile848Thr variant. In two families, the variant was shown to segregate with disease. The p.Ile848Thr variant was absent from 350 control subjects and is not found in the Genome Aggregation Database, in a region of good sequence coverage, so the variant is presumed to be rare. Functional studies in C-fibers from a patient carrying the p.Ile848Thr variant demonstrated an enhanced early subnormal conduction in the velocity recovery cycles (Namer et al. 2015). In addition, HEK293 cells expressing this variant exhibited altered sodium channel function compared to wild type (Cummins et al. 2004). Based on the collective evidence and application of the ACMG criteria, the p.Ile848Thr variant is classified as pathogenic for SCN9A-related peripheral neuropathies associated with increased pain. -

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 848 of the SCN9A protein (p.Ile848Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant primary erythromelalgia (PMID: 14985375, 29911575). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6350). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN9A protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SCN9A function (PMID: 15385606). For these reasons, this variant has been classified as Pathogenic. -

Acute episodes of neuropathic symptoms;C4023691:Abnormality of pain sensation Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;.;.;D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;M;.;.;M;M;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.8	D;D;.;.;.;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.;.;.;D;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;D;.
Vest4		0.93
MutPred		0.94		Loss of stability (P = 0.0229);.;Loss of stability (P = 0.0229);Loss of stability (P = 0.0229);.;.;.;
MVP		0.95
MPC		0.38
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.83
gMVP		0.93

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

Other links and lift over

dbSNP: rs80356474; hg19: chr2-167133791; COSMIC: COSV57598870; COSMIC: COSV57598870;