rs13414203

Positions:

• chr2-166288632-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001365536.1(SCN9A):​c.1119T>C​(p.Ala373=) 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

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

Verdict is Benign. Variant got -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 id is 130254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166288632-A-G is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1119T>C	p.Ala373=	synonymous_variant	10/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.1030-5933A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1119T>C	p.Ala373=	synonymous_variant	10/27		NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1708-5933A>G		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.367 AC: 88292 AN: 240754 Hom.: 16579 AF XY: 0.368 AC XY: 48071 AN XY: 130640

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 SAS exome AF: 0.355

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

Gnomad4 AFR exome AF: 0.376

Gnomad4 AMR exome AF: 0.279

Gnomad4 ASJ exome AF: 0.354

Gnomad4 EAS exome AF: 0.306

Gnomad4 SAS exome AF: 0.355

Gnomad4 FIN exome AF: 0.417

Gnomad4 NFE exome AF: 0.396

Gnomad4 OTH exome AF: 0.379

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

Gnomad4 AFR AF: 0.379

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.310

Gnomad4 SAS AF: 0.356

Gnomad4 FIN AF: 0.414

Gnomad4 NFE AF: 0.403

Gnomad4 OTH AF: 0.367

Alfa AF: 0.389 Hom.: 7235

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 24, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inherited Erythromelalgia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Primary erythromelalgia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Paroxysmal extreme pain disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs13414203; hg19: chr2-167145142; COSMIC: COSV57621345;