rs200174262

Variant names:

• chr2-166281778-G-A
• rs200174262
• NM_001365536.1:c.2005C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166281778-G-A
• chr2-166281778-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R669H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.232

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]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• 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: {Uncertain_significance=2, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2005C>T	p.Arg669Cys	missense_variant	Exon 13 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2005C>T	p.Arg669Cys	missense_variant	Exon 13 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2005C>T	p.Arg669Cys	missense_variant	Exon 13 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1972C>T	p.Arg658Cys	missense_variant	Exon 13 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1972C>T	p.Arg658Cys	missense_variant	Exon 13 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1972C>T	p.Arg658Cys	missense_variant	Exon 13 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 51 AN: 151924 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000117 AC: 29 AN: 247644 AF XY: 0.0000968

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000637 AC: 93 AN: 1460354 Hom.: 0 Cov.: 30 AF XY: 0.0000496 AC XY: 36 AN XY: 726410

Gnomad4 AFR exome AF: 0.00105 AC: 35 AN: 33394

Gnomad4 AMR exome AF: 0.0000672 AC: 3 AN: 44642

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26086

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39606

Gnomad4 SAS exome AF: 0.0000581 AC: 5 AN: 86082

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53260

Gnomad4 NFE exome AF: 0.0000378 AC: 42 AN: 1111210

Gnomad4 Remaining exome AF: 0.000133 AC: 8 AN: 60318

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74316

Gnomad4 AFR AF: 0.00116 AC: 0.00115702 AN: 0.00115702

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000294187 AN: 0.0000294187

Gnomad4 OTH AF: 0.000475 AC: 0.000474834 AN: 0.000474834

Alfa AF: 0.000250 Hom.: 0

Bravo AF: 0.000427

ESP6500AA AF: 0.00134 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 23, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 18, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.79	.;D;.;.;D;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.42	T;.;T;T;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.031	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.8	.;M;.;.;M;M;.
PrimateAI	Benign	0.35	T
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	T
GERP RS		2.7
Varity_R		0.14
gMVP		0.46
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs200174262; hg19: chr2-167138288;