2-166251825-C-T

Variant names:

• chr2-166251825-C-T
• rs748920376
• NM_001365536.1:c.3412G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365536.1(SCN9A):​c.3412G>A​(p.Gly1138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,520 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. G1138E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.01
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18382943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3412G>A	p.Gly1138Arg	missense_variant	Exon 18 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3412G>A	p.Gly1138Arg	missense_variant	Exon 18 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.3412G>A	p.Gly1138Arg	missense_variant	Exon 18 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.3379G>A	p.Gly1127Arg	missense_variant	Exon 18 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.3379G>A	p.Gly1127Arg	missense_variant	Exon 18 of 27			ENSP00000495983.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248230 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460520 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726522

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111162

Other (OTH) AF: 0.00 AC: 0 AN: 60288

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000295 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000828 AC: 1

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

May 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1127 of the SCN9A protein (p.Gly1127Arg). This variant is present in population databases (rs748920376, gnomAD 0.006%). 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: 569568). 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	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.30	.;T;.;.;T;.
Eigen	Benign	-0.027
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;.;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.4	.;L;.;.;L;L
PhyloP100		3.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.0	N;.;.;.;.;N
REVEL	Benign	0.21
Sift	Benign	0.033	D;.;.;.;.;D
Sift4G	Benign	0.33	T;T;.;.;.;T
Vest4		0.24
MutPred		0.41		Gain of solvent accessibility (P = 0.0012);.;Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);.;.;
MVP		0.72
MPC		0.23
ClinPred		0.26	T
GERP RS		4.7
Varity_R		0.32
gMVP		0.26
Mutation Taster		=65/35	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: rs748920376; hg19: chr2-167108335; COSMIC: COSV105146428;