rs75230218

Positions:

• chr2-166233466-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365536.1(SCN9A):​c.3802-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0782 in 1,558,058 control chromosomes in the GnomAD database, including 5,283 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (375 hom., cov: 31)
  • Exomes 𝑓: 0.080 (4908 hom.)
• Consequence: SCN9A NM_001365536.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001690
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.529

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-166233466-T-C is Benign according to our data. Variant chr2-166233466-T-C is described in ClinVar as [Benign]. Clinvar id is 130266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166233466-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.3802-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.612-14729T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.3802-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1290-14729T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0656 AC: 9958 AN: 151736 Hom.: 375 Cov.: 31

Gnomad AFR AF: 0.0370

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.0735

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.0774

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0892

Gnomad OTH AF: 0.0695

GnomAD3 exomes AF: 0.0652 AC: 13016 AN: 199656 Hom.: 511 AF XY: 0.0650 AC XY: 7122 AN XY: 109624

Gnomad AFR exome AF: 0.0358

Gnomad AMR exome AF: 0.0369

Gnomad ASJ exome AF: 0.0739

Gnomad EAS exome AF: 0.0151

Gnomad SAS exome AF: 0.0264

Gnomad FIN exome AF: 0.0808

Gnomad NFE exome AF: 0.0864

Gnomad OTH exome AF: 0.0679

GnomAD4 exome AF: 0.0795 AC: 111857 AN: 1406204 Hom.: 4908 Cov.: 28 AF XY: 0.0781 AC XY: 54516 AN XY: 698430

Gnomad4 AFR exome AF: 0.0342

Gnomad4 AMR exome AF: 0.0392

Gnomad4 ASJ exome AF: 0.0742

Gnomad4 EAS exome AF: 0.00842

Gnomad4 SAS exome AF: 0.0254

Gnomad4 FIN exome AF: 0.0804

Gnomad4 NFE exome AF: 0.0885

Gnomad4 OTH exome AF: 0.0757

GnomAD4 genome AF: 0.0656 AC: 9959 AN: 151854 Hom.: 375 Cov.: 31 AF XY: 0.0632 AC XY: 4688 AN XY: 74204

Gnomad4 AFR AF: 0.0369

Gnomad4 AMR AF: 0.0583

Gnomad4 ASJ AF: 0.0735

Gnomad4 EAS AF: 0.0139

Gnomad4 SAS AF: 0.0206

Gnomad4 FIN AF: 0.0774

Gnomad4 NFE AF: 0.0892

Gnomad4 OTH AF: 0.0688

Alfa AF: 0.0828 Hom.: 182

Bravo AF: 0.0626

Asia WGS AF: 0.0160 AC: 55 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)	Apr 04, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	-	- -

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 04, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

Inherited Erythromelalgia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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	-0.74
CADD	Benign	5.4
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.070
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: rs75230218; hg19: chr2-167089976; COSMIC: COSV104409026;