rs1553488787

Variant names:

• chr2-166280418-A-T
• rs1553488787
• NM_001365536.1:c.2282T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001365536.1(SCN9A):​c.2282T>A​(p.Met761Lys) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2282T>A	p.Met761Lys	missense_variant	Exon 14 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2282T>A	p.Met761Lys	missense_variant	Exon 14 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2282T>A	p.Met761Lys	missense_variant	Exon 14 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2249T>A	p.Met750Lys	missense_variant	Exon 14 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2249T>A	p.Met750Lys	missense_variant	Exon 14 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.2249T>A	p.Met750Lys	missense_variant	Exon 14 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 12, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine with lysine at codon 750 of the SCN9A protein (p.Met750Lys). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and lysine. This variant is not present in population databases (ExAC no frequency). In summary, this variant has uncertain impact on SCN9A function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 an SCN9A-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;D;.;.;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	.;H;.;.;H;H;.
PhyloP100		9.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.8	D;.;.;.;.;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;D;.
Vest4		0.97
MutPred		0.71		Gain of ubiquitination at M750 (P = 0.0325);.;Gain of ubiquitination at M750 (P = 0.0325);Gain of ubiquitination at M750 (P = 0.0325);.;.;Gain of ubiquitination at M750 (P = 0.0325);
MVP		0.95
MPC		0.69
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.80
Mutation Taster		=3/97	disease causing

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

Other links and lift over

dbSNP: rs1553488787; hg19: chr2-167136928;