rs200391162

Positions:

chr2-166288642-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001365536.1(SCN9A):c.1109C>T(p.Thr370Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000202 in 1,536,110 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T370T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

SCN9A
NM_001365536.1 missense, splice_region

Scores

Splicing: ADA: 0.9820

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 10.0

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 14: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, dbscSNV1_ADA, dbscSNV1_RF, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.1109C>T	p.Thr370Met	missense_variant, splice_region_variant	10/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 link	c.1109C>T	p.Thr370Met	missense_variant, splice_region_variant	10/27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 link	c.1109C>T	p.Thr370Met	missense_variant, splice_region_variant	10/27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 link	c.1109C>T	p.Thr370Met	missense_variant, splice_region_variant	10/27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 link	c.1109C>T	p.Thr370Met	missense_variant, splice_region_variant	10/27			ENSP00000495983.1	Q15858-4
SCN9A	ENST00000454569.6 link	c.1109C>T	p.Thr370Met	missense_variant, splice_region_variant	10/15	1		ENSP00000413212.2	A0A0C4DG82
SCN9A	ENST00000452182.2 link	c.1109C>T	p.Thr370Met	missense_variant, splice_region_variant	11/11	1		ENSP00000393141.2	H7C064

Frequencies

GnomAD3 genomes

AF:

0.000658

AC:

100

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000409

AC:

AN:

215386

Hom.:

AF XY:

0.000417

AC XY:

AN XY:

117418

show subpopulations

Gnomad AFR exome

AF:

0.00245

Gnomad AMR exome

AF:

0.0000408

Gnomad ASJ exome

AF:

0.000128

Gnomad EAS exome

AF:

0.00138

Gnomad SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000974

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000152

AC:

211

AN:

1383984

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

115

AN XY:

683128

show subpopulations

Gnomad4 AFR exome

AF:

0.00196

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.000130

Gnomad4 EAS exome

AF:

0.000360

Gnomad4 SAS exome

AF:

0.00112

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000317

Gnomad4 OTH exome

AF:

0.000194

GnomAD4 genome

AF:

0.000657

AC:

100

AN:

152126

Hom.:

Cov.:

AF XY:

0.000767

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00205

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000401

Hom.:

Bravo

AF:

0.000793

ESP6500AA

AF:

0.00248

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000455

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 26, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2023	Reported previously as a likely pathogenic variant in trans (on different alleles) with a second likely pathogenic variant in a patient with hypertrichotic osteochondrodysplasia; however, this patient also harbored a pathogenic variant in a different gene that was thought to explain the phenotype (Salfati et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31847883) -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2020

The p.T370M variant (also known as c.1109C>T), located in coding exon 9 of the SCN9A gene, results from a C to T substitution at nucleotide position 1109. The threonine at codon 370 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of primary erythermalgia/small fiber neuropathy, and paroxysmal extreme pain disorder; however, its contribution to the development of congenital insensitivity to pain and hereditary sensory autonomic neuropathy type II is uncertain. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

.;D;.;.;D;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.13

T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;M;M;.;M;M;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.9

D;.;.;.;.;D;.;.

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;.;.;.;.;D;.;.

Sift4G

Uncertain

0.0040

D;D;.;.;.;D;.;.

Polyphen

1.0

.;D;.;.;D;.;.;.

Vest4

0.82

MVP

0.94

MPC

0.57

ClinPred

0.18

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.83

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