2-166304225-A-G

Variant names:

• chr2-166304225-A-G
• rs74449889
• NM_001365536.1:c.688+13T>C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The NM_001365536.1(SCN9A):​c.688+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,612,160 control chromosomes in the GnomAD database, including 2,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (223 hom., cov: 32)
  • Exomes 𝑓: 0.015 (1869 hom.)
• Consequence: SCN9A NM_001365536.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.727

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.15).
• BP6: Variant 2-166304225-A-G is Benign according to our data. Variant chr2-166304225-A-G is described in ClinVar as [Benign]. Clinvar id is 139076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166304225-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.688+13T>C		intron_variant	Intron 6 of 26	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.688+13T>C		intron_variant	Intron 6 of 26		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.688+13T>C		intron_variant	Intron 6 of 26	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.688+13T>C		intron_variant	Intron 6 of 26	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.597-103T>C		intron_variant	Intron 5 of 26			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.688+13T>C		intron_variant	Intron 6 of 14	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.688+13T>C		intron_variant	Intron 7 of 10	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3257 AN: 152090 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00413

Gnomad OTH AF: 0.0248

GnomAD3 exomes AF: 0.0486 AC: 12134 AN: 249452 Hom.: 1269 AF XY: 0.0396 AC XY: 5351 AN XY: 135244

Gnomad AFR exome AF: 0.00379

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.00766

Gnomad EAS exome AF: 0.132

Gnomad SAS exome AF: 0.0160

Gnomad FIN exome AF: 0.00898

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.0348

GnomAD4 exome AF: 0.0153 AC: 22366 AN: 1459950 Hom.: 1869 Cov.: 31 AF XY: 0.0143 AC XY: 10387 AN XY: 726370

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.224

Gnomad4 ASJ exome AF: 0.00739

Gnomad4 EAS exome AF: 0.154

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.00811

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.0171

GnomAD4 genome AF: 0.0215 AC: 3267 AN: 152210 Hom.: 223 Cov.: 32 AF XY: 0.0243 AC XY: 1812 AN XY: 74432

Gnomad4 AFR AF: 0.00363

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.00952

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.00413

Gnomad4 OTH AF: 0.0250

Alfa AF: 0.00520 Hom.: 2

Bravo AF: 0.0316

Asia WGS AF: 0.0670 AC: 234 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 27% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 25. Only high quality variants are reported. -

Feb 18, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary erythromelalgia Benign:1

Jan 12, 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. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1

Jan 12, 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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Small fiber neuropathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal extreme pain disorder Benign:1

Jan 12, 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	-0.15
CADD	Benign	17
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74449889; hg19: chr2-167160735; COSMIC: COSV57611217; COSMIC: COSV57611217;