rs200174262

Positions:

chr2-166281778-G-A

Variant summary

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

The NM_001365536.1(SCN9A):c.2005C>T(p.Arg669Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000893 in 1,612,396 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R669R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.232

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=0.030504197).

BP6

Variant 2-166281778-G-A is Benign according to our data. Variant chr2-166281778-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449780.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	Protein	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.2005C>T	p.Arg669Cys	missense_variant	13/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1 linkuse as main transcript	n.1029+4531G>A		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.2005C>T	p.Arg669Cys	missense_variant	13/27		NM_001365536.1	ENSP00000495601	P1	Q15858-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.1707+4531G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000336

AC:

AN:

151924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

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:

0.0000294

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000117

AC:

AN:

247644

Hom.:

AF XY:

0.0000968

AC XY:

AN XY:

134336

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000659

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000356

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000637

AC:

AN:

1460354

Hom.:

Cov.:

AF XY:

0.0000496

AC XY:

AN XY:

726410

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000581

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000335

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00116

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:

0.0000294

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000147

Hom.:

Bravo

AF:

0.000427

ESP6500AA

AF:

0.00134

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The p.R658C variant (also known as c.1972C>T), located in coding exon 12 of the SCN9A gene, results from a C to T substitution at nucleotide position 1972. The arginine at codon 658 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species, and cysteine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is unlikely to be causative of primary erythermalgia/small fiber neuropathy and paroxysmal extreme pain disorder (PEPD); however, its contribution to the development of congenital insensitivity to pain (CIP) and hereditary sensory autonomic neuropathy type II (HSAN2D) is uncertain. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 23, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 18, 2024

Variant summary: SCN9A c.1972C>T (p.Arg658Cys) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 247644 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN9A causing Channelopathy-Associated Congenital Insensitivity To Pain, Autosomal Recessive phenotype (0.0011). To our knowledge, no occurrence of c.1972C>T in individuals affected with Channelopathy-Associated Congenital Insensitivity To Pain, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 449780). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.79

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

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.42

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

M_CAP

Benign

0.054

MetaRNN

Benign

0.031

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

MetaSVM

Uncertain

0.57

MutationAssessor

Uncertain

2.8

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.8

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

REVEL

Uncertain

0.38

Sift

Benign

0.032

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

Sift4G

Uncertain

0.023

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

Polyphen

0.014

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

Vest4

0.42

MVP

0.81

MPC

0.17

ClinPred

0.071

GERP RS

2.7

Varity_R

0.14

gMVP

0.46

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