rs121908910

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_001365536.1(SCN9A):c.3019C>T(p.Arg1007Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000189 in 1,584,382 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1007H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.31

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-166272731-G-A is Pathogenic according to our data. Variant chr2-166272731-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6356.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}. Variant chr2-166272731-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.3019C>T	p.Arg1007Cys	missense_variant	17/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1 linkuse as main transcript	n.870-4357G>A		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.3019C>T	p.Arg1007Cys	missense_variant	17/27		NM_001365536.1	P1	Q15858-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.1548-4357G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151586

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

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:

0.00

GnomAD3 exomes

AF:

0.0000176

AC:

AN:

226882

Hom.:

AF XY:

0.0000245

AC XY:

AN XY:

122620

show subpopulations

Gnomad AFR exome

AF:

0.0000665

Gnomad AMR exome

AF:

0.0000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000589

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000949

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000195

AC:

AN:

1432680

Hom.:

Cov.:

AF XY:

0.0000225

AC XY:

AN XY:

709628

show subpopulations

Gnomad4 AFR exome

AF:

0.0000312

Gnomad4 AMR exome

AF:

0.0000746

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.0000182

Gnomad4 OTH exome

AF:

0.0000339

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151702

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74092

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000132

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:

0.00

Alfa

AF:

0.0000883

Hom.:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Paroxysmal extreme pain disorder

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 07, 2006	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Aug 12, 2021	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 09, 2023

For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is not expected to disrupt SCN9A protein function. ClinVar contains an entry for this variant (Variation ID: 6356). This missense change has been observed in individuals with autosomal dominant paroxysmal extreme pain disorder (PMID: 17145499). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121908910, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 996 of the SCN9A protein (p.Arg996Cys). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 28, 2023

Identified in an individual with epilepsy in published literature; however, no further clinical or segregation information was provided (Truty et al., 2019); 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: 34426522, 17145499, 31440721) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Uncertain

-0.030

Cadd

Benign

Dann

Benign

0.79

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.58

T;.;T;T;T;T

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.57

D;D;D;D;D;D

MetaSVM

Benign

-0.37

MutationTaster

Benign

0.00010

A;A;A;A

PrimateAI

Benign

0.19

PROVEAN

Uncertain

-2.6

D;.;.;.;.;D

REVEL

Uncertain

0.57

Sift

Benign

0.094

T;.;.;.;.;T

Sift4G

Benign

0.19

T;T;.;.;.;T

Vest4

0.24

MVP

0.61

MPC

0.18

ClinPred

0.18

GERP RS

3.6

Varity_R

0.17

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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