2-166251875-C-T

Variant names:

• chr2-166251875-C-T
• rs74401238
• NM_001365536.1:c.3362G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365536.1(SCN9A):​c.3362G>A​(p.Arg1121Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,611,986 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1121W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (51 hom., cov: 32)
  • Exomes 𝑓: 0.019 (323 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.86
• Publications: 13 publications found

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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002156794).
• BP6: Variant 2-166251875-C-T is Benign according to our data. Variant chr2-166251875-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0219 (3332/151996) while in subpopulation SAS AF = 0.0278 (134/4814). AF 95% confidence interval is 0.0249. There are 51 homozygotes in GnomAd4. There are 1752 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 AD,SD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3362G>A	p.Arg1121Gln	missense_variant	Exon 18 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3362G>A	p.Arg1121Gln	missense_variant	Exon 18 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.3362G>A	p.Arg1121Gln	missense_variant	Exon 18 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.3329G>A	p.Arg1110Gln	missense_variant	Exon 18 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.3329G>A	p.Arg1110Gln	missense_variant	Exon 18 of 27			ENSP00000495983.1

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3329 AN: 151878 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0274

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0204 AC: 5064 AN: 247896 AF XY: 0.0218

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.00866

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.000224

Gnomad FIN exome AF: 0.0385

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0188 AC: 27471 AN: 1459990 Hom.: 323 Cov.: 31 AF XY: 0.0193 AC XY: 13983 AN XY: 726258

African (AFR) AF: 0.0289 AC: 965 AN: 33394

American (AMR) AF: 0.00898 AC: 400 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 388 AN: 26080

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39612

South Asian (SAS) AF: 0.0283 AC: 2442 AN: 86178

European-Finnish (FIN) AF: 0.0346 AC: 1846 AN: 53336

Middle Eastern (MID) AF: 0.0344 AC: 198 AN: 5760

European-Non Finnish (NFE) AF: 0.0182 AC: 20239 AN: 1110836

Other (OTH) AF: 0.0163 AC: 984 AN: 60246

GnomAD4 genome AF: 0.0219 AC: 3332 AN: 151996 Hom.: 51 Cov.: 32 AF XY: 0.0236 AC XY: 1752 AN XY: 74278

African (AFR) AF: 0.0261 AC: 1085 AN: 41492

American (AMR) AF: 0.0106 AC: 161 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5152

South Asian (SAS) AF: 0.0278 AC: 134 AN: 4814

European-Finnish (FIN) AF: 0.0419 AC: 444 AN: 10586

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.0204 AC: 1388 AN: 67950

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0192 Hom.: 67

Bravo AF: 0.0196

TwinsUK AF: 0.0167 AC: 62

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.0326 AC: 123

ESP6500EA AF: 0.0195 AC: 160

ExAC AF: 0.0202 AC: 2441

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0177

EpiControl AF: 0.0188

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Nov 04, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 21, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Primary erythromelalgia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Small fiber neuropathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal extreme pain disorder Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.3
DANN	Benign	0.60
DEOGEN2	Benign	0.17	.;T;.;.;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.51	T;.;T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.35	.;N;.;.;N;N
PhyloP100		-3.9
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.88	N;.;.;.;.;N
REVEL	Benign	0.12
Sift	Benign	0.58	T;.;.;.;.;T
Sift4G	Benign	0.78	T;T;.;.;.;T
Vest4		0.15
MPC		0.14
ClinPred		0.0019	T
GERP RS		-2.9
Varity_R		0.025
gMVP		0.25
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74401238; hg19: chr2-167108385;