2-166198848-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001365536.1(SCN9A):c.5791G>C(p.Asp1931His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1931V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.357

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010671705).

BP6

Variant 2-166198848-C-G is Benign according to our data. Variant chr2-166198848-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448296.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.5791G>C	p.Asp1931His	missense_variant	27/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1 linkuse as main transcript	n.432-791C>G		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.5791G>C	p.Asp1931His	missense_variant	27/27		NM_001365536.1	P1	Q15858-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.1110-791C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

191

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00437

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000288

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:

0.000273

AC:

AN:

248784

Hom.:

AF XY:

0.000244

AC XY:

AN XY:

135004

show subpopulations

Gnomad AFR exome

AF:

0.00407

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

156

AN:

1461474

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.00397

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.00125

AC:

191

AN:

152214

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00436

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.000288

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:

0.0000638

Hom.:

Bravo

AF:

0.00135

ESP6500AA

AF:

0.00389

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.000331

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 26, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 27, 2017

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2020

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. -

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

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

Cadd

Benign

Dann

Benign

0.86

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.58

T;.;T;T;T;T

M_CAP

Benign

0.071

MetaRNN

Benign

0.011

T;T;T;T;T;T

MetaSVM

Uncertain

0.22

MutationTaster

Benign

0.80

N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.8

D;.;.;.;.;D

REVEL

Uncertain

0.34

Sift

Benign

0.034

D;.;.;.;.;D

Sift4G

Uncertain

0.045

D;D;.;.;.;D

Vest4

0.069

MVP

0.57

MPC

0.14

ClinPred

0.021

GERP RS

5.2

Varity_R

0.095

gMVP

0.51

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