rs4525717

Positions:

• chr2-166280610-C-T

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.2105-15G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,450,794 control chromosomes in the GnomAD database, including 15,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1598 hom., cov: 32)
  • Exomes 𝑓: 0.14 (13855 hom.)
• Consequence: SCN9A NM_001365536.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.142

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=-0.83).
• BP6: Variant 2-166280610-C-T is Benign according to our data. Variant chr2-166280610-C-T is described in ClinVar as [Benign]. Clinvar id is 167660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166280610-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.2105-15G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.1029+3363C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.2105-15G>A		splice_polypyrimidine_tract_variant, intron_variant			NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1707+3363C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20518 AN: 152030 Hom.: 1600 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.121

GnomAD3 exomes AF: 0.156 AC: 24834 AN: 159548 Hom.: 2380 AF XY: 0.159 AC XY: 13435 AN XY: 84292

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0965

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.368

Gnomad SAS exome AF: 0.192

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.139 AC: 180127 AN: 1298646 Hom.: 13855 Cov.: 19 AF XY: 0.140 AC XY: 90339 AN XY: 645746

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.0973

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.356

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.135 AC: 20518 AN: 152148 Hom.: 1598 Cov.: 32 AF XY: 0.139 AC XY: 10320 AN XY: 74396

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.358

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.181

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.125

Alfa AF: 0.124 Hom.: 254

Bravo AF: 0.129

Asia WGS AF: 0.254 AC: 882 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 20, 2014	- -

Inherited Erythromelalgia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Primary erythromelalgia Benign:1

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:1

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

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Paroxysmal extreme pain disorder Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.14
DANN	Benign	0.58

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: rs4525717; hg19: chr2-167137120; COSMIC: COSV57619236; COSMIC: COSV57619236;