2-166272746-C-A

Position:

chr2-166272746-C-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BA1

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:15

Conservation

PhyloP100: -0.491

Variant links:

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]

SCN9A links:

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

SCN1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, Uncertain_significance=1, Benign=11}. 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 linkuse as main transcript	c.3004G>T	p.Val1002Leu	missense_variant	17/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1 linkuse as main transcript	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 linkuse as main transcript	c.3004G>T	p.Val1002Leu	missense_variant	17/27		NM_001365536.1	P1	Q15858-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.1548-4342C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2191

AN:

151674

Hom.:

108

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.00835

AC XY:

5824

AN XY:

697362

show subpopulations

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.:

AF XY:

0.0159

AC XY:

1181

AN XY:

74126

show subpopulations

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:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00221

AC:

ESP6500EA

AF:

0.00418

AC:

ExAC

AF:

0.0290

AC:

3502

Asia WGS

AF:

0.0310

AC:

106

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
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:1Benign:2

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	- -
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. -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.30

.;T;.;.;T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.78

T;.;T;T;T;T

MetaRNN

Benign

0.0019

T;T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.4

.;L;.;.;L;L

MutationTaster

Benign

0.94

P;P;P;P

PrimateAI

Benign

0.33

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over