2-166199711-G-T

Variant names:

• chr2-166199711-G-T
• rs879253994
• NM_001365536.1:c.4928C>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001365536.1(SCN9A):​c.4928C>A​(p.Ala1643Glu) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1643P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.86
• Publications: 27 publications found

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

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 2-166199711-G-T is Pathogenic according to our data. Variant chr2-166199711-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 245903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.4928C>A	p.Ala1643Glu	missense_variant	Exon 27 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.4928C>A	p.Ala1643Glu	missense_variant	Exon 27 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.4928C>A	p.Ala1643Glu	missense_variant	Exon 27 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.4895C>A	p.Ala1632Glu	missense_variant	Exon 27 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.4895C>A	p.Ala1632Glu	missense_variant	Exon 27 of 27			ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paroxysmal extreme pain disorder Pathogenic:2

Nov 16, 2021

Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 13, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 25, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The A1632E missense variant in the SCN9A gene has been reported previously as a de novo variant in a patient with characteristics of both inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD) (Estacion et al., 2008). Functional analysis shows that A1632E alters channel function and results in neuronal hyperexciability (Estacion et al., 2008). The A1632E variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a non-conservative amino acid substitution that occurs at a highly conserved position in between the S4 and S5 transmembrane segments of the forth homologous domain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;.;.;D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	.;H;.;.;H;H
PhyloP100		9.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.5	D;.;.;.;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;.;D
Vest4		0.93
MutPred		0.91		Gain of relative solvent accessibility (P = 0.1259);.;Gain of relative solvent accessibility (P = 0.1259);.;.;.;
MVP		0.96
MPC		0.60
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879253994; hg19: chr2-167056221;