rs149707354

Variant names:

• chr2-166278265-T-A
• rs149707354
• NM_001365536.1:c.2392A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166278265-T-A
• chr2-166278265-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365536.1(SCN9A):​c.2392A>T​(p.Met798Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. M798V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.64
• Publications: 7 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16703561).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2392A>T	p.Met798Leu	missense_variant	Exon 15 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2392A>T	p.Met798Leu	missense_variant	Exon 15 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2392A>T	p.Met798Leu	missense_variant	Exon 15 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2359A>T	p.Met787Leu	missense_variant	Exon 15 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2359A>T	p.Met787Leu	missense_variant	Exon 15 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.2359A>T	p.Met787Leu	missense_variant	Exon 15 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459534 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725988

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 85896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110976

Other (OTH) AF: 0.0000166 AC: 1 AN: 60314

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 6

Bravo AF: 0.00000378

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

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 787 of the SCN9A protein (p.Met787Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. ClinVar contains an entry for this variant (Variation ID: 2062983). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SCN9A protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Benign	0.84
DEOGEN2	Uncertain	0.49	.;T;.;.;T;.;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;.;T;T;T;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.051	D
MutationAssessor	Benign	-1.7	.;N;.;.;N;N;.;.
PhyloP100		2.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;.;.;.;.;N;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.38	T;.;.;.;.;T;.;.
Sift4G	Benign	1.0	T;T;.;.;.;T;.;.
Vest4		0.34
MutPred		0.58		Gain of catalytic residue at M787 (P = 0.0249);.;Gain of catalytic residue at M787 (P = 0.0249);Gain of catalytic residue at M787 (P = 0.0249);.;.;.;Gain of catalytic residue at M787 (P = 0.0249);
MVP		0.60
MPC		0.11
ClinPred		0.53	D
GERP RS		4.0
PromoterAI		0.00010	Neutral
Varity_R		0.28
gMVP		0.44
Mutation Taster		=31/69	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: rs149707354; hg19: chr2-167134775;