rs13414203

Variant names:

• chr2-166288632-A-G
• rs13414203
• NM_001365536.1:c.1119T>C

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.1119T>C​(p.Ala373Ala) 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 1,588,578 control chromosomes in the GnomAD database, including 119,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11116 hom., cov: 31)
  • Exomes 𝑓: 0.39 (108323 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.08
• 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=-0.41).
• BP6: Variant 2-166288632-A-G is Benign according to our data. Variant chr2-166288632-A-G is described in ClinVar as Benign. ClinVar VariationId is 130254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.08 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.1119T>C	p.Ala373Ala	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.1119T>C	p.Ala373Ala	synonymous_variant	Exon 10 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1119T>C	p.Ala373Ala	synonymous_variant	Exon 10 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1119T>C	p.Ala373Ala	synonymous_variant	Exon 10 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1119T>C	p.Ala373Ala	synonymous_variant	Exon 10 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1119T>C	p.Ala373Ala	synonymous_variant	Exon 10 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.1119T>C	p.Ala373Ala	synonymous_variant	Exon 11 of 11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57848 AN: 151844 Hom.: 11120 Cov.: 31

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.368

GnomAD2 exomes AF: 0.367 AC: 88292 AN: 240754 AF XY: 0.368

Gnomad AFR exome AF: 0.377

Gnomad AMR exome AF: 0.273

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.316

Gnomad FIN exome AF: 0.416

Gnomad NFE exome AF: 0.395

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.386 AC: 554591 AN: 1436616 Hom.: 108323 Cov.: 34 AF XY: 0.385 AC XY: 274355 AN XY: 712816

African (AFR) AF: 0.376 AC: 12326 AN: 32772

American (AMR) AF: 0.279 AC: 12056 AN: 43192

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 8972 AN: 25372

East Asian (EAS) AF: 0.306 AC: 12064 AN: 39422

South Asian (SAS) AF: 0.355 AC: 29127 AN: 82080

European-Finnish (FIN) AF: 0.417 AC: 21948 AN: 52688

Middle Eastern (MID) AF: 0.305 AC: 1721 AN: 5644

European-Non Finnish (NFE) AF: 0.396 AC: 433924 AN: 1096214

Other (OTH) AF: 0.379 AC: 22453 AN: 59232

GnomAD4 genome AF: 0.381 AC: 57869 AN: 151962 Hom.: 11116 Cov.: 31 AF XY: 0.378 AC XY: 28043 AN XY: 74282

African (AFR) AF: 0.379 AC: 15726 AN: 41454

American (AMR) AF: 0.318 AC: 4842 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1235 AN: 3468

East Asian (EAS) AF: 0.310 AC: 1597 AN: 5146

South Asian (SAS) AF: 0.356 AC: 1716 AN: 4814

European-Finnish (FIN) AF: 0.414 AC: 4367 AN: 10556

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.403 AC: 27379 AN: 67972

Other (OTH) AF: 0.367 AC: 773 AN: 2108

Alfa AF: 0.389 Hom.: 9771

Bravo AF: 0.372

Asia WGS AF: 0.352 AC: 1231 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

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

- -

Feb 24, 2015

Eurofins Ntd Llc (ga)

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 44% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 41. 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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

May 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

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

- -

Inherited Erythromelalgia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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
BayesDel_noAF	Benign	-0.41
CADD	Benign	10
DANN	Benign	0.76
PhyloP100		1.1
Mutation Taster		=94/6	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: rs13414203; hg19: chr2-167145142; COSMIC: COSV57621345;