chr2-166272746-C-A

Variant names:

• chr2-166272746-C-A
• rs4369876
• NM_001365536.1:c.3004G>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001365536.1(SCN9A):​c.3004G>T​(p.Val1002Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00941 in 1,563,390 control chromosomes in the GnomAD database, including 899 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.014 (109 hom., cov: 31)
  • Exomes 𝑓: 0.0089 (790 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: -0.491

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019373894).
• BP6: Variant 2-166272746-C-A is Benign according to our data. Variant chr2-166272746-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94090.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=11, Uncertain_significance=1}. Variant chr2-166272746-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3004G>T	p.Val1002Leu	missense_variant	Exon 17 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3004G>T	p.Val1002Leu	missense_variant	Exon 17 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.3004G>T	p.Val1002Leu	missense_variant	Exon 17 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2971G>T	p.Val991Leu	missense_variant	Exon 17 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2971G>T	p.Val991Leu	missense_variant	Exon 17 of 27			ENSP00000495983.1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2191 AN: 151674 Hom.: 108 Cov.: 31

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0958

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0568

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.000285

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.0332 AC: 6843 AN: 206416 Hom.: 629 AF XY: 0.0269 AC XY: 2990 AN XY: 111038

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.0590

Gnomad SAS exome AF: 0.0111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00269

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.00886 AC: 12507 AN: 1411598 Hom.: 790 Cov.: 31 AF XY: 0.00835 AC XY: 5824 AN XY: 697362

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.175

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.0504

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.000156

Gnomad4 NFE exome AF: 0.00239

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.0145 AC: 2200 AN: 151792 Hom.: 109 Cov.: 31 AF XY: 0.0159 AC XY: 1181 AN XY: 74126

Gnomad4 AFR AF: 0.00273

Gnomad4 AMR AF: 0.0960

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0569

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.000285

Gnomad4 NFE AF: 0.00337

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00993 Hom.: 106

Bravo AF: 0.0235

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00221 AC: 8

ESP6500EA AF: 0.00418 AC: 34

ExAC AF: 0.0290 AC: 3502

Asia WGS AF: 0.0310 AC: 106 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Aug 01, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 21. Only high quality variants are reported. -

not provided Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25585270, 27956748, 26284228, 27535533, 21698661) -

Primary erythromelalgia Uncertain:1 Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Val991Leu variant in SCN9A has been identified in an individual suspected to have small fibre neuropathy (PMID: 21698661). In vitro functional studies provide some evidence that the p.Pro124Ser variant will not impact protein function (PMID: 21698661). However, these types of assays may not accurately represent biological function. This variant is classified as benign for autosomal dominant small fibre neuropathy because it has been identified in >20% of Latino chromosomes, including 340 homozygotes, by ExAC (http://gnomad.broadinstitute.org/). -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Small fiber neuropathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal extreme pain disorder Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.30	.;T;.;.;T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.78	T;.;T;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	.;L;.;.;L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.9	N;.;.;.;.;N
REVEL	Benign	0.17
Sift	Benign	0.10	T;.;.;.;.;T
Sift4G	Benign	0.31	T;T;.;.;.;T
Vest4		0.49
MutPred		0.71		Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;
MPC		0.12
ClinPred		0.0014	T
GERP RS		-0.95
Varity_R		0.19
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs4369876; hg19: chr2-167129256; COSMIC: COSV57600591; COSMIC: COSV57600591;