2-166311583-C-T

Variant names:

• chr2-166311583-C-T
• rs6432901
• NM_001365536.1:c.174G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001365536.1(SCN9A):​c.174G>A​(p.Gln58Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 1,612,054 control chromosomes in the GnomAD database, including 313,422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31209 hom., cov: 25)
  • Exomes 𝑓: 0.62 (282213 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.0820
• Publications: 21 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-166311583-C-T is Benign according to our data. Variant chr2-166311583-C-T is described in ClinVar as Benign. ClinVar VariationId is 130259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.082 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.174G>A	p.Gln58Gln	synonymous_variant	Exon 2 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.174G>A	p.Gln58Gln	synonymous_variant	Exon 2 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.174G>A	p.Gln58Gln	synonymous_variant	Exon 2 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.174G>A	p.Gln58Gln	synonymous_variant	Exon 2 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.174G>A	p.Gln58Gln	synonymous_variant	Exon 2 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.174G>A	p.Gln58Gln	synonymous_variant	Exon 2 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.174G>A	p.Gln58Gln	synonymous_variant	Exon 3 of 11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes AF: 0.637 AC: 95890 AN: 150528 Hom.: 31188 Cov.: 25

Gnomad AFR AF: 0.749

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.636

GnomAD2 exomes AF: 0.576 AC: 143655 AN: 249532 AF XY: 0.577

Gnomad AFR exome AF: 0.753

Gnomad AMR exome AF: 0.455

Gnomad ASJ exome AF: 0.511

Gnomad EAS exome AF: 0.434

Gnomad FIN exome AF: 0.535

Gnomad NFE exome AF: 0.633

Gnomad OTH exome AF: 0.585

GnomAD4 exome AF: 0.618 AC: 903294 AN: 1461408 Hom.: 282213 Cov.: 46 AF XY: 0.616 AC XY: 447929 AN XY: 726996

African (AFR) AF: 0.746 AC: 24976 AN: 33472

American (AMR) AF: 0.467 AC: 20876 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 13421 AN: 26126

East Asian (EAS) AF: 0.426 AC: 16909 AN: 39700

South Asian (SAS) AF: 0.542 AC: 46705 AN: 86212

European-Finnish (FIN) AF: 0.541 AC: 28879 AN: 53388

Middle Eastern (MID) AF: 0.548 AC: 3157 AN: 5764

European-Non Finnish (NFE) AF: 0.640 AC: 711325 AN: 1111670

Other (OTH) AF: 0.614 AC: 37046 AN: 60358

GnomAD4 genome AF: 0.637 AC: 95952 AN: 150646 Hom.: 31209 Cov.: 25 AF XY: 0.628 AC XY: 46177 AN XY: 73484

African (AFR) AF: 0.749 AC: 30721 AN: 41016

American (AMR) AF: 0.552 AC: 8341 AN: 15112

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1749 AN: 3456

East Asian (EAS) AF: 0.424 AC: 2130 AN: 5022

South Asian (SAS) AF: 0.546 AC: 2596 AN: 4758

European-Finnish (FIN) AF: 0.532 AC: 5506 AN: 10342

Middle Eastern (MID) AF: 0.559 AC: 162 AN: 290

European-Non Finnish (NFE) AF: 0.633 AC: 42837 AN: 67658

Other (OTH) AF: 0.632 AC: 1318 AN: 2086

Alfa AF: 0.633 Hom.: 67378

Bravo AF: 0.640

Asia WGS AF: 0.498 AC: 1734 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 73% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 68. Only high quality variants are reported. -

-

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. -

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Primary erythromelalgia Benign:2

Jan 12, 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. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

Paroxysmal extreme pain disorder Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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 04, 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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.8
DANN	Benign	0.67
PhyloP100		-0.082
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6432901; hg19: chr2-167168093; COSMIC: COSV57601199;