rs1553491169

Positions:

• chr2-166288553-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001365536.1(SCN9A):​c.1198G>A​(p.Val400Met) 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. 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:2 O:1
• Conservation: PhyloP100: 7.84

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:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 2-166288553-C-T is Pathogenic according to our data. Variant chr2-166288553-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 538468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1198G>A	p.Val400Met	missense_variant	10/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1198G>A	p.Val400Met	missense_variant	10/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1198G>A	p.Val400Met	missense_variant	10/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1198G>A	p.Val400Met	missense_variant	10/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1198G>A	p.Val400Met	missense_variant	10/27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1198G>A	p.Val400Met	missense_variant	10/15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jun 20, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN9A function (PMID: 19557861, 23149731). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 538468). This missense change has been observed in individuals with autosomal dominant primary erythromelalgia (PMID: 19557861, 33688580). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 400 of the SCN9A protein (p.Val400Met). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2020

- -

Primary erythromelalgia Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;.;.;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	5.1	H;H;H;.;H;H;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.0	D;.;.;.;.;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.;.;.;.;D;.
Sift4G	Uncertain	0.019	D;D;.;.;.;D;.
Polyphen		1.0	.;D;.;.;D;.;.
Vest4		0.97
MVP		0.93
MPC		0.56
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.67

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: rs1553491169; hg19: chr2-167145063; COSMIC: COSV57620397; COSMIC: COSV57620397;