chr2-166272820-G-C

Position:

• chr2-166272820-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001365536.1(SCN9A):​c.2930C>G​(p.Thr977Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000439 in 1,366,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 10.0

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4050845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2930C>G	p.Thr977Arg	missense_variant	17/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.870-4268G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2930C>G	p.Thr977Arg	missense_variant	17/27		NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1548-4268G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000576 AC: 1 AN: 173648 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 91462

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000485

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000439 AC: 6 AN: 1366624 Hom.: 0 Cov.: 31 AF XY: 0.00000299 AC XY: 2 AN XY: 670010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000344

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: 0.00000374

Gnomad4 OTH exome AF: 0.0000178

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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 28, 2023

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 966 of the SCN9A protein (p.Thr966Arg). This variant is present in population databases (no rsID available, gnomAD 0.005%). 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: 538441). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 30, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	.;D;.;.;D;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.41	T;T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.9	.;L;.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N;.;.;.;.;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;.;.;.;.;D
Sift4G	Uncertain	0.056	T;T;.;.;.;T
Vest4		0.29
MutPred		0.32		Gain of solvent accessibility (P = 0.0058);.;Gain of solvent accessibility (P = 0.0058);Gain of solvent accessibility (P = 0.0058);.;.;
MVP		0.91
MPC		0.20
ClinPred		0.89	D
GERP RS		5.4
Varity_R		0.75
gMVP		0.52

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: rs1369602144; hg19: chr2-167129330;