rs6747673

Positions:

• chr2-166288464-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001365536.1(SCN9A):​c.1287T>A​(p.Arg429Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,601,758 control chromosomes in the GnomAD database, including 195,323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24861 hom., cov: 31)
  • Exomes 𝑓: 0.48 (170462 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.447

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-166288464-A-T is Benign according to our data. Variant chr2-166288464-A-T is described in ClinVar as [Benign]. Clinvar id is 130257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166288464-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.447 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1287T>A	p.Arg429Arg	synonymous_variant	10/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1287T>A	p.Arg429Arg	synonymous_variant	10/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1287T>A	p.Arg429Arg	synonymous_variant	10/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1287T>A	p.Arg429Arg	synonymous_variant	10/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1287T>A	p.Arg429Arg	synonymous_variant	10/27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1287T>A	p.Arg429Arg	synonymous_variant	10/15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84583 AN: 151694 Hom.: 24822 Cov.: 31

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.548

GnomAD3 exomes AF: 0.493 AC: 122267 AN: 247868 Hom.: 31120 AF XY: 0.484 AC XY: 65130 AN XY: 134470

Gnomad AFR exome AF: 0.761

Gnomad AMR exome AF: 0.540

Gnomad ASJ exome AF: 0.504

Gnomad EAS exome AF: 0.381

Gnomad SAS exome AF: 0.440

Gnomad FIN exome AF: 0.488

Gnomad NFE exome AF: 0.475

Gnomad OTH exome AF: 0.487

GnomAD4 exome AF: 0.480 AC: 696049 AN: 1449946 Hom.: 170462 Cov.: 33 AF XY: 0.478 AC XY: 344784 AN XY: 721474

Gnomad4 AFR exome AF: 0.766

Gnomad4 AMR exome AF: 0.534

Gnomad4 ASJ exome AF: 0.504

Gnomad4 EAS exome AF: 0.384

Gnomad4 SAS exome AF: 0.441

Gnomad4 FIN exome AF: 0.484

Gnomad4 NFE exome AF: 0.475

Gnomad4 OTH exome AF: 0.491

GnomAD4 genome AF: 0.558 AC: 84685 AN: 151812 Hom.: 24861 Cov.: 31 AF XY: 0.553 AC XY: 41008 AN XY: 74194

Gnomad4 AFR AF: 0.753

Gnomad4 AMR AF: 0.526

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.381

Gnomad4 SAS AF: 0.436

Gnomad4 FIN AF: 0.488

Gnomad4 NFE AF: 0.486

Gnomad4 OTH AF: 0.546

Alfa AF: 0.509 Hom.: 6630

Bravo AF: 0.566

Asia WGS AF: 0.445 AC: 1552 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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 58% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 54. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Eurofins Ntd Llc (ga)	Jul 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

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

Primary erythromelalgia Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Paroxysmal extreme pain disorder Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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

- -

Small fiber neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.5
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs6747673; hg19: chr2-167144974; COSMIC: COSV57611204; COSMIC: COSV57611204;