2-166233466-T-C

Variant names:

• chr2-166233466-T-C
• rs75230218
• NM_001365536.1:c.3802-4A>G

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.001690
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.529
• Publications: 5 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 -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.
• 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 rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3802-4A>G		splice_region_variant, intron_variant	Intron 20 of 26	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3802-4A>G		splice_region_variant, intron_variant	Intron 20 of 26		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.3802-4A>G		splice_region_variant, intron_variant	Intron 20 of 26	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.3769-4A>G		splice_region_variant, intron_variant	Intron 20 of 26	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.3769-4A>G		splice_region_variant, intron_variant	Intron 20 of 26			ENSP00000495983.1

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

GnomAD2 exomes AF: 0.0652 AC: 13016 AN: 199656 AF XY: 0.0650

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 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

African (AFR) AF: 0.0342 AC: 1024 AN: 29922

American (AMR) AF: 0.0392 AC: 1152 AN: 29408

Ashkenazi Jewish (ASJ) AF: 0.0742 AC: 1804 AN: 24304

East Asian (EAS) AF: 0.00842 AC: 319 AN: 37870

South Asian (SAS) AF: 0.0254 AC: 1901 AN: 74732

European-Finnish (FIN) AF: 0.0804 AC: 4242 AN: 52778

Middle Eastern (MID) AF: 0.0484 AC: 272 AN: 5622

European-Non Finnish (NFE) AF: 0.0885 AC: 96742 AN: 1093442

Other (OTH) AF: 0.0757 AC: 4401 AN: 58126

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

African (AFR) AF: 0.0369 AC: 1529 AN: 41454

American (AMR) AF: 0.0583 AC: 889 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0735 AC: 255 AN: 3470

East Asian (EAS) AF: 0.0139 AC: 72 AN: 5166

South Asian (SAS) AF: 0.0206 AC: 99 AN: 4810

European-Finnish (FIN) AF: 0.0774 AC: 816 AN: 10536

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0892 AC: 6049 AN: 67844

Other (OTH) AF: 0.0688 AC: 145 AN: 2108

Alfa AF: 0.0814 Hom.: 252

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

Apr 04, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

May 04, 2018

Athena Diagnostics

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

- -

Mar 03, 2015

GeneDx

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. -

Inherited Erythromelalgia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.74
CADD	Benign	5.4
DANN	Benign	0.88
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs75230218; hg19: chr2-167089976;