2-166311504-T-C

Variant names:

• chr2-166311504-T-C
• rs200885240
• NM_001365536.1:c.253A>G

Variant summary

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

The NM_001365536.1(SCN9A):​c.253A>G​(p.Lys85Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,296 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.253A>G	p.Lys85Glu	missense_variant	Exon 2 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.253A>G	p.Lys85Glu	missense_variant	Exon 2 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.253A>G	p.Lys85Glu	missense_variant	Exon 2 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.253A>G	p.Lys85Glu	missense_variant	Exon 2 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.253A>G	p.Lys85Glu	missense_variant	Exon 2 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.253A>G	p.Lys85Glu	missense_variant	Exon 2 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.253A>G	p.Lys85Glu	missense_variant	Exon 3 of 11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406296 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 695180

African (AFR) AF: 0.00 AC: 0 AN: 32112

American (AMR) AF: 0.00 AC: 0 AN: 41042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24242

East Asian (EAS) AF: 0.00 AC: 0 AN: 39178

South Asian (SAS) AF: 0.00 AC: 0 AN: 74566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4868

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1080984

Other (OTH) AF: 0.00 AC: 0 AN: 57628

GnomAD4 genome Cov.: 24

Alfa AF: 0.0000355 Hom.: 0

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 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 85 of the SCN9A protein (p.Lys85Glu). 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: 574457). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN9A protein function. 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	0.17
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T;.;.;T;.;.;.
Eigen	Benign	0.096
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.6	M;M;M;.;M;M;.;.
PhyloP100		1.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.5	N;N;.;.;.;N;.;.
REVEL	Uncertain	0.52
Sift	Benign	0.035	D;D;.;.;.;D;.;.
Sift4G	Benign	0.23	T;T;.;.;.;T;.;.
Vest4		0.53
MVP		0.78
MPC		0.19
ClinPred		0.91	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.34
Mutation Taster		=50/50

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: rs200885240; hg19: chr2-167168014;