rs1258991294

Variant names:

• chr2-166286589-A-G
• rs1258991294
• NM_001365536.1:c.1349T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-166286589-A-G
• chr2-166286589-A-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001365536.1(SCN9A):​c.1349T>C​(p.Ile450Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,429,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. I450V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.35
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040522426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1349T>C	p.Ile450Thr	missense_variant	Exon 11 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1349T>C	p.Ile450Thr	missense_variant	Exon 11 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1349T>C	p.Ile450Thr	missense_variant	Exon 11 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1349T>C	p.Ile450Thr	missense_variant	Exon 11 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1349T>C	p.Ile450Thr	missense_variant	Exon 11 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1349T>C	p.Ile450Thr	missense_variant	Exon 11 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000945 AC: 2 AN: 211740 AF XY: 0.00000873

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000736

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1429980 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 709260

African (AFR) AF: 0.00 AC: 0 AN: 31658

American (AMR) AF: 0.0000535 AC: 2 AN: 37398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24734

East Asian (EAS) AF: 0.00 AC: 0 AN: 39382

South Asian (SAS) AF: 0.00 AC: 0 AN: 79944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100268

Other (OTH) AF: 0.00 AC: 0 AN: 59020

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN9A c.1349T>C (p.Ile450Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.4e-06 in 211740 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1349T>C in individuals affected with Channelopathy-Associated Congenital Insensitivity To Pain, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 471083). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Jun 30, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I450T variant (also known as c.1349T>C), located in coding exon 10 of the SCN9A gene, results from a T to C substitution at nucleotide position 1349. The isoleucine at codon 450 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with threonine at codon 450 of the SCN9A protein (p.Ile450Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. 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 tolerated. 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	0.12
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.16	.;T;.;.;T;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.62	T;.;T;T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.041	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	-0.69	N;N;N;.;N;N;.
PhyloP100		1.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.25	N;.;.;.;.;N;.
REVEL	Benign	0.18
Sift	Benign	0.41	T;.;.;.;.;T;.
Sift4G	Benign	0.57	T;T;.;.;.;T;.
Polyphen		0.0	.;B;.;.;B;.;.
Vest4		0.13
MVP		0.45
MPC		0.15
ClinPred		0.029	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.081
Mutation Taster		=73/27	polymorphism

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: rs1258991294; hg19: chr2-167143099;