rs200945460

Positions:

• chr2-166280508-A-G
• chr2-166280508-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001365536.1(SCN9A):​c.2192T>C​(p.Ile731Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,437,076 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I731K) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-166280508-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2192T>C	p.Ile731Thr	missense_variant	14/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2192T>C	p.Ile731Thr	missense_variant	14/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2192T>C	p.Ile731Thr	missense_variant	14/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2159T>C	p.Ile720Thr	missense_variant	14/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2159T>C	p.Ile720Thr	missense_variant	14/27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.2159T>C	p.Ile720Thr	missense_variant	14/15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000472 AC: 1 AN: 212026 Hom.: 0 AF XY: 0.00000879 AC XY: 1 AN XY: 113744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000109

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1437076 Hom.: 0 Cov.: 31 AF XY: 0.00000562 AC XY: 4 AN XY: 712282

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000455

Gnomad4 OTH exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 23, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 720 of the SCN9A protein (p.Ile720Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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	0.29
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;D;.;.;D;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T;.;T;T;T;T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.3	.;M;.;.;M;M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.4	D;.;.;.;.;D;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;.;.;.;.;D;.
Sift4G	Uncertain	0.042	D;D;.;.;.;D;.
Vest4		0.63
MVP		0.91
MPC		0.17
ClinPred		0.93	D
GERP RS		5.9
Varity_R		0.69
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs200945460; hg19: chr2-167137018;