2-166303111-C-T

Position:

• chr2-166303111-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365536.1(SCN9A):​c.880G>A​(p.Glu294Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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: 0.0340

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]

SCN9A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15117323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.880G>A	p.Glu294Lys	missense_variant	7/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.880G>A	p.Glu294Lys	missense_variant	7/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.880G>A	p.Glu294Lys	missense_variant	7/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.880G>A	p.Glu294Lys	missense_variant	7/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.880G>A	p.Glu294Lys	missense_variant	7/27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.880G>A	p.Glu294Lys	missense_variant	7/15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.880G>A	p.Glu294Lys	missense_variant	8/11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451492 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721296

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 03, 2018

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, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an SCN9A-related disease. This sequence change replaces glutamic acid with lysine at codon 294 of the SCN9A protein (p.Glu294Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	12
DANN	Benign	0.62
DEOGEN2	Uncertain	0.45	.;T;.;.;T;.;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.68	T;.;T;T;T;T;T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.69	N;N;N;.;N;N;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.74	N;.;.;.;.;N;.;.
REVEL	Uncertain	0.41
Sift	Benign	0.84	T;.;.;.;.;T;.;.
Sift4G	Benign	0.71	T;T;.;.;.;T;.;.
Polyphen		0.0	.;B;.;.;B;.;.;.
Vest4		0.16
MVP		0.56
MPC		0.13
ClinPred		0.080	T
GERP RS		3.1
Varity_R		0.27
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553495086; hg19: chr2-167159621;