2-166242648-A-G

Position:

chr2-166242648-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001365536.1(SCN9A):c.3481T>C(p.Trp1161Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,548,672 control chromosomes in the GnomAD database, including 587,761 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 Benign (★★).

Frequency

Genomes: 𝑓 0.88 ( 58696 hom., cov: 30)

Exomes 𝑓: 0.87 ( 529065 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.38

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=2.3442258E-6).

BP6

Variant 2-166242648-A-G is Benign according to our data. Variant chr2-166242648-A-G is described in ClinVar as [Benign]. Clinvar id is 440255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166242648-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.3481T>C	p.Trp1161Arg	missense_variant	19/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1 linkuse as main transcript	n.612-5547A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2 linkuse as main transcript	c.3481T>C	p.Trp1161Arg	missense_variant	19/27		NM_001365536.1	ENSP00000495601	P1	Q15858-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.1290-5547A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.878

AC:

133444

AN:

151908

Hom.:

58658

Cov.:

show subpopulations

Gnomad AFR

AF:

0.893

Gnomad AMI

AF:

0.867

Gnomad AMR

AF:

0.882

Gnomad ASJ

AF:

0.914

Gnomad EAS

AF:

0.951

Gnomad SAS

AF:

0.834

Gnomad FIN

AF:

0.887

Gnomad MID

AF:

0.883

Gnomad NFE

AF:

0.864

Gnomad OTH

AF:

0.871

GnomAD3 exomes

AF:

0.880

AC:

138994

AN:

158010

Hom.:

61211

AF XY:

0.878

AC XY:

72950

AN XY:

83122

show subpopulations

Gnomad AFR exome

AF:

0.892

Gnomad AMR exome

AF:

0.902

Gnomad ASJ exome

AF:

0.912

Gnomad EAS exome

AF:

0.956

Gnomad SAS exome

AF:

0.842

Gnomad FIN exome

AF:

0.893

Gnomad NFE exome

AF:

0.862

Gnomad OTH exome

AF:

0.875

GnomAD4 exome

AF:

0.870

AC:

1215240

AN:

1396646

Hom.:

529065

Cov.:

AF XY:

0.869

AC XY:

598906

AN XY:

688988

show subpopulations

Gnomad4 AFR exome

AF:

0.893

Gnomad4 AMR exome

AF:

0.897

Gnomad4 ASJ exome

AF:

0.910

Gnomad4 EAS exome

AF:

0.950

Gnomad4 SAS exome

AF:

0.842

Gnomad4 FIN exome

AF:

0.894

Gnomad4 NFE exome

AF:

0.866

Gnomad4 OTH exome

AF:

0.877

GnomAD4 genome

AF:

0.878

AC:

133538

AN:

152026

Hom.:

58696

Cov.:

AF XY:

0.877

AC XY:

65188

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.893

Gnomad4 AMR

AF:

0.882

Gnomad4 ASJ

AF:

0.914

Gnomad4 EAS

AF:

0.951

Gnomad4 SAS

AF:

0.833

Gnomad4 FIN

AF:

0.887

Gnomad4 NFE

AF:

0.864

Gnomad4 OTH

AF:

0.870

Alfa

AF:

0.871

Hom.:

107171

Bravo

AF:

0.882

TwinsUK

AF:

0.873

AC:

3238

ALSPAC

AF:

0.866

AC:

3338

ESP6500AA

AF:

0.891

AC:

3274

ESP6500EA

AF:

0.871

AC:

7029

ExAC

AF:

0.852

AC:

64740

Asia WGS

AF:

0.884

AC:

3076

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 96% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 89. Only high quality variants are reported. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary erythromelalgia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

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

- -

Paroxysmal extreme pain disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.17

.;T;.;.;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.035

T;.;T;T;T;T

MetaRNN

Benign

0.0000023

T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-3.3

.;N;.;.;N;N

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

5.2

N;.;.;.;.;N

REVEL

Benign

0.15

Sift

Benign

1.0

T;.;.;.;.;T

Sift4G

Benign

1.0

T;T;.;.;.;T

Vest4

0.044

MutPred

0.54

Gain of disorder (P = 0.0309);.;Gain of disorder (P = 0.0309);Gain of disorder (P = 0.0309);.;.;

MPC

0.21

ClinPred

0.0020

GERP RS

3.8

Varity_R

0.098

gMVP

0.28

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