chr2-166242623-T-G

Position:

chr2-166242623-T-G

Variant summary

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

The NM_001365536.1(SCN9A):c.3506A>C(p.Asn1169Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,552,992 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 2 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.431

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:):

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=0.007779449).

BP6

Variant 2-166242623-T-G is Benign according to our data. Variant chr2-166242623-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 194947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00199 (303/152168) while in subpopulation AFR AF= 0.00701 (291/41528). AF 95% confidence interval is 0.00635. There are 1 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.3506A>C	p.Asn1169Thr	missense_variant	19/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 linkuse as main transcript	c.3506A>C	p.Asn1169Thr	missense_variant	19/27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 linkuse as main transcript	c.3506A>C	p.Asn1169Thr	missense_variant	19/27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 linkuse as main transcript	c.3473A>C	p.Asn1158Thr	missense_variant	19/27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 linkuse as main transcript	c.3473A>C	p.Asn1158Thr	missense_variant	19/27			ENSP00000495983.1	Q15858-4

Frequencies

GnomAD3 genomes

AF:

0.00199

AC:

303

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00703

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000591

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000478

AC:

AN:

160972

Hom.:

AF XY:

0.000284

AC XY:

AN XY:

84642

show subpopulations

Gnomad AFR exome

AF:

0.00764

Gnomad AMR exome

AF:

0.000322

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000875

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000315

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000191

AC:

268

AN:

1400824

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

100

AN XY:

691134

show subpopulations

Gnomad4 AFR exome

AF:

0.00665

Gnomad4 AMR exome

AF:

0.000363

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000505

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.000637

GnomAD4 genome

AF:

0.00199

AC:

303

AN:

152168

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

138

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00701

Gnomad4 AMR

AF:

0.000590

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000311

Hom.:

Bravo

AF:

0.00216

ESP6500AA

AF:

0.00525

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000392

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SCN9A: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2020	This variant is associated with the following publications: (PMID: 22581653) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 02, 2015

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SCN9A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

.;D;.;.;D;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.20

LIST_S2

Uncertain

0.96

D;.;D;D;D;D

M_CAP

Benign

0.079

MetaRNN

Benign

0.0078

T;T;T;T;T;T

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.6

.;M;.;.;M;M

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.7

D;.;.;.;.;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.010

D;.;.;.;.;D

Sift4G

Uncertain

0.059

T;T;.;.;.;T

Vest4

0.29

MVP

0.62

MPC

0.17

ClinPred

0.056

GERP RS

2.3

Varity_R

0.27

gMVP

0.16

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