rs149207258

Positions:

• chr2-166199827-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001365536.1(SCN9A):​c.4812G>T​(p.Val1604Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0766 in 1,613,646 control chromosomes in the GnomAD database, including 5,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (369 hom., cov: 31)
  • Exomes 𝑓: 0.078 (4893 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.0770

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:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-166199827-C-A is Benign according to our data. Variant chr2-166199827-C-A is described in ClinVar as [Benign]. Clinvar id is 130270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166199827-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.4812G>T	p.Val1604Val	synonymous_variant	27/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.4812G>T	p.Val1604Val	synonymous_variant	27/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.4812G>T	p.Val1604Val	synonymous_variant	27/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.4779G>T	p.Val1593Val	synonymous_variant	27/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.4779G>T	p.Val1593Val	synonymous_variant	27/27			ENSP00000495983.1

Frequencies

GnomAD3 genomes AF: 0.0646 AC: 9802 AN: 151768 Hom.: 369 Cov.: 31

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0566

Gnomad ASJ AF: 0.0706

Gnomad EAS AF: 0.0143

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.0776

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0878

Gnomad OTH AF: 0.0670

GnomAD3 exomes AF: 0.0616 AC: 15485 AN: 251428 Hom.: 597 AF XY: 0.0616 AC XY: 8367 AN XY: 135886

Gnomad AFR exome AF: 0.0347

Gnomad AMR exome AF: 0.0356

Gnomad ASJ exome AF: 0.0730

Gnomad EAS exome AF: 0.0153

Gnomad SAS exome AF: 0.0266

Gnomad FIN exome AF: 0.0805

Gnomad NFE exome AF: 0.0854

Gnomad OTH exome AF: 0.0670

GnomAD4 exome AF: 0.0779 AC: 113849 AN: 1461760 Hom.: 4893 Cov.: 33 AF XY: 0.0764 AC XY: 55537 AN XY: 727194

Gnomad4 AFR exome AF: 0.0333

Gnomad4 AMR exome AF: 0.0373

Gnomad4 ASJ exome AF: 0.0727

Gnomad4 EAS exome AF: 0.00887

Gnomad4 SAS exome AF: 0.0258

Gnomad4 FIN exome AF: 0.0804

Gnomad4 NFE exome AF: 0.0877

Gnomad4 OTH exome AF: 0.0743

GnomAD4 genome AF: 0.0645 AC: 9803 AN: 151886 Hom.: 369 Cov.: 31 AF XY: 0.0622 AC XY: 4613 AN XY: 74220

Gnomad4 AFR AF: 0.0364

Gnomad4 AMR AF: 0.0565

Gnomad4 ASJ AF: 0.0706

Gnomad4 EAS AF: 0.0142

Gnomad4 SAS AF: 0.0196

Gnomad4 FIN AF: 0.0776

Gnomad4 NFE AF: 0.0877

Gnomad4 OTH AF: 0.0664

Alfa AF: 0.0792 Hom.: 230

Bravo AF: 0.0616

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.0862

EpiControl AF: 0.0792

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

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	-	- -

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. -

Inherited Erythromelalgia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149207258; hg19: chr2-167056337; COSMIC: COSV57627632;