2-166284752-C-T

Position:

chr2-166284752-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001365536.1(SCN9A):c.1675G>A(p.Gly559Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.87

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4145926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.1675G>A	p.Gly559Ser	missense_variant	12/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 link	c.1675G>A	p.Gly559Ser	missense_variant	12/27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 link	c.1675G>A	p.Gly559Ser	missense_variant	12/27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 link	c.1675G>A	p.Gly559Ser	missense_variant	12/27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 link	c.1675G>A	p.Gly559Ser	missense_variant	12/27			ENSP00000495983.1	Q15858-4
SCN9A	ENST00000454569.6 link	c.1675G>A	p.Gly559Ser	missense_variant	12/15	1		ENSP00000413212.2	A0A0C4DG82

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000884

AC:

AN:

248790

Hom.:

AF XY:

0.0000815

AC XY:

AN XY:

134968

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000186

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000144

AC:

210

AN:

1461584

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000179

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000118

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000179

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000259

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000827

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 26, 2019

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2019

The p.G559S variant (also known as c.1675G>A), located in coding exon 11 of the SCN9A gene, results from a G to A substitution at nucleotide position 1675. The glycine at codon 559 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 08, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 559 of the SCN9A protein (p.Gly559Ser). This variant is present in population databases (rs201569378, gnomAD 0.02%). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 23895530). ClinVar contains an entry for this variant (Variation ID: 430171). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN9A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2022

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: 35886038, 23895530) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

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

Eigen

Benign

0.054

Eigen_PC

Benign

0.067

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.069

MetaRNN

Benign

0.41

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

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.2

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

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.3

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

REVEL

Uncertain

0.53

Sift

Benign

0.037

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

Sift4G

Benign

0.35

T;T;.;.;.;T;.

Polyphen

0.33

.;B;.;.;B;.;.

Vest4

0.36

MVP

0.69

MPC

0.14

ClinPred

0.16

GERP RS

4.8

Varity_R

0.21

gMVP

0.60

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