rs4369876

chr2-166272746-C-Achr2-166272746-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1002M) has been classified as Uncertain significance.

• 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:14
• 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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 8 uncertain in NM_001365536.1
• 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=10, 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/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.3004G>T	p.Val1002Leu	missense_variant	17/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.870-4342C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.3004G>T	p.Val1002Leu	missense_variant	17/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1548-4342C>A		intron_variant, non_coding_transcript_variant

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:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2018	This variant is associated with the following publications: (PMID: 25585270, 27956748, 26284228, 27535533, 21698661) -

Primary erythromelalgia Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	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/). -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Small fiber neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Paroxysmal extreme pain disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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
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
MutationTaster	Benign	0.94	P;P;P;P
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;