2-166288485-T-C

Variant names:

• chr2-166288485-T-C
• rs13402180
• NM_001365536.1:c.1266A>G

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.1266A>G​(p.Glu422Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,606,194 control chromosomes in the GnomAD database, including 121,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11102 hom., cov: 31)
  • Exomes 𝑓: 0.39 (110372 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 2.06
• Publications: 20 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=-0.46).
• BP6: Variant 2-166288485-T-C is Benign according to our data. Variant chr2-166288485-T-C is described in ClinVar as Benign. ClinVar VariationId is 130256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1266A>G	p.Glu422Glu	synonymous_variant	Exon 10 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1266A>G	p.Glu422Glu	synonymous_variant	Exon 10 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1266A>G	p.Glu422Glu	synonymous_variant	Exon 10 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1266A>G	p.Glu422Glu	synonymous_variant	Exon 10 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1266A>G	p.Glu422Glu	synonymous_variant	Exon 10 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1266A>G	p.Glu422Glu	synonymous_variant	Exon 10 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.*130A>G		downstream_gene_variant		1		ENSP00000393141.2

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57827 AN: 151752 Hom.: 11106 Cov.: 31

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.367 AC: 91314 AN: 248628 AF XY: 0.368

Gnomad AFR exome AF: 0.378

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.319

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.386 AC: 561984 AN: 1454324 Hom.: 110372 Cov.: 35 AF XY: 0.385 AC XY: 279002 AN XY: 723768

African (AFR) AF: 0.377 AC: 12573 AN: 33336

American (AMR) AF: 0.281 AC: 12551 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 9264 AN: 26064

East Asian (EAS) AF: 0.307 AC: 12151 AN: 39644

South Asian (SAS) AF: 0.358 AC: 30755 AN: 85950

European-Finnish (FIN) AF: 0.418 AC: 22275 AN: 53352

Middle Eastern (MID) AF: 0.307 AC: 1763 AN: 5746

European-Non Finnish (NFE) AF: 0.396 AC: 437877 AN: 1105444

Other (OTH) AF: 0.379 AC: 22775 AN: 60116

GnomAD4 genome AF: 0.381 AC: 57848 AN: 151870 Hom.: 11102 Cov.: 31 AF XY: 0.377 AC XY: 28010 AN XY: 74200

African (AFR) AF: 0.379 AC: 15701 AN: 41414

American (AMR) AF: 0.319 AC: 4857 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1238 AN: 3470

East Asian (EAS) AF: 0.311 AC: 1601 AN: 5152

South Asian (SAS) AF: 0.357 AC: 1721 AN: 4824

European-Finnish (FIN) AF: 0.413 AC: 4349 AN: 10522

Middle Eastern (MID) AF: 0.253 AC: 74 AN: 292

European-Non Finnish (NFE) AF: 0.403 AC: 27373 AN: 67934

Other (OTH) AF: 0.368 AC: 774 AN: 2104

Alfa AF: 0.389 Hom.: 22920

Bravo AF: 0.372

Asia WGS AF: 0.352 AC: 1231 AN: 3476

EpiCase AF: 0.397

EpiControl AF: 0.384

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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 42% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 39. Only high quality variants are reported. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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. -

Feb 24, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 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

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. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive 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

- -

Paroxysmal extreme pain disorder 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

- -

Inherited Erythromelalgia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs13402180; hg19: chr2-167144995; COSMIC: COSV57621333; COSMIC: COSV57621333;