2-166305834-C-T

Position:

chr2-166305834-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365536.1(SCN9A):c.554G>A(p.Arg185His) variant causes a missense change. The variant allele was found at a frequency of 0.0024 in 1,613,182 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 6 hom., cov: 31)

Exomes 𝑓: 0.0021 ( 9 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2B:13

Conservation

PhyloP100: 6.16

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01727277).

BP6

Variant 2-166305834-C-T is Benign according to our data. Variant chr2-166305834-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 157596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166305834-C-T is described in Lovd as [Benign]. Variant chr2-166305834-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00541 (821/151808) while in subpopulation AFR AF= 0.0138 (572/41408). AF 95% confidence interval is 0.0129. There are 6 homozygotes in gnomad4. There are 386 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.554G>A	p.Arg185His	missense_variant	5/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2 linkuse as main transcript	c.554G>A	p.Arg185His	missense_variant	5/27		NM_001365536.1	ENSP00000495601	P1	Q15858-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.1977+9705C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00541

AC:

820

AN:

151690

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00171

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00559

Gnomad SAS

AF:

0.000832

Gnomad FIN

AF:

0.00218

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00221

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00280

AC:

698

AN:

249044

Hom.:

AF XY:

0.00261

AC XY:

353

AN XY:

135114

show subpopulations

Gnomad AFR exome

AF:

0.0137

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00417

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.00288

Gnomad NFE exome

AF:

0.00253

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00209

AC:

3049

AN:

1461374

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

1450

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.0130

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00219

Gnomad4 SAS exome

AF:

0.000742

Gnomad4 FIN exome

AF:

0.00272

Gnomad4 NFE exome

AF:

0.00185

Gnomad4 OTH exome

AF:

0.00345

GnomAD4 genome

AF:

0.00541

AC:

821

AN:

151808

Hom.:

Cov.:

AF XY:

0.00520

AC XY:

386

AN XY:

74208

show subpopulations

Gnomad4 AFR

AF:

0.0138

Gnomad4 AMR

AF:

0.00171

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00560

Gnomad4 SAS

AF:

0.000833

Gnomad4 FIN

AF:

0.00218

Gnomad4 NFE

AF:

0.00221

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00249

Hom.:

Bravo

AF:

0.00541

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.0135

AC:

ESP6500EA

AF:

0.00219

AC:

ExAC

AF:

0.00330

AC:

399

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 11, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SCN9A: BS1, BS2 -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 31, 2023	- -

Small fiber neuropathy

Pathogenic:1Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Paroxysmal extreme pain disorder

Pathogenic:1Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2014	- -
Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Primary erythromelalgia

Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

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

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

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

MetaRNN

Benign

0.017

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

MetaSVM

Uncertain

0.68

MutationAssessor

Pathogenic

3.8

H;H;H;.;H;H;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.8

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

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.92

MVP

0.92

MPC

0.62

ClinPred

0.11

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.91

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