2-166311583-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001365536.1(SCN9A):c.174G>A(p.Gln58=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 1,612,054 control chromosomes in the GnomAD database, including 313,422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31209 hom., cov: 25)
  • Exomes 𝑓: 0.62 (282213 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.0820

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-166311583-C-T is Benign according to our data. Variant chr2-166311583-C-T is described in ClinVar as [Benign]. Clinvar id is 130259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166311583-C-T is described in Lovd as [Benign]. Variant chr2-166311583-C-T is described in Lovd as [Pathogenic].
• BP7: Synonymous conserved (PhyloP=-0.082 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.174G>A	p.Gln58=	synonymous_variant	2/27	ENST00000642356.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.174G>A	p.Gln58=	synonymous_variant	2/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1977+15454C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.637 AC: 95890 AN: 150528 Hom.: 31188 Cov.: 25

Gnomad AFR AF: 0.749

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.636

GnomAD3 exomes AF: 0.576 AC: 143655 AN: 249532 Hom.: 42542 AF XY: 0.577 AC XY: 78043 AN XY: 135372

Gnomad AFR exome AF: 0.753

Gnomad AMR exome AF: 0.455

Gnomad ASJ exome AF: 0.511

Gnomad EAS exome AF: 0.434

Gnomad SAS exome AF: 0.542

Gnomad FIN exome AF: 0.535

Gnomad NFE exome AF: 0.633

Gnomad OTH exome AF: 0.585

GnomAD4 exome AF: 0.618 AC: 903294 AN: 1461408 Hom.: 282213 Cov.: 46 AF XY: 0.616 AC XY: 447929 AN XY: 726996

Gnomad4 AFR exome AF: 0.746

Gnomad4 AMR exome AF: 0.467

Gnomad4 ASJ exome AF: 0.514

Gnomad4 EAS exome AF: 0.426

Gnomad4 SAS exome AF: 0.542

Gnomad4 FIN exome AF: 0.541

Gnomad4 NFE exome AF: 0.640

Gnomad4 OTH exome AF: 0.614

GnomAD4 genome AF: 0.637 AC: 95952 AN: 150646 Hom.: 31209 Cov.: 25 AF XY: 0.628 AC XY: 46177 AN XY: 73484

Gnomad4 AFR AF: 0.749

Gnomad4 AMR AF: 0.552

Gnomad4 ASJ AF: 0.506

Gnomad4 EAS AF: 0.424

Gnomad4 SAS AF: 0.546

Gnomad4 FIN AF: 0.532

Gnomad4 NFE AF: 0.633

Gnomad4 OTH AF: 0.632

Alfa AF: 0.626 Hom.: 40121

Bravo AF: 0.640

Asia WGS AF: 0.498 AC: 1734 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Primary erythromelalgia Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 06, 2018	- -

Paroxysmal extreme pain disorder Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

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

- -

Small fiber neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	6.8
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs6432901; hg19: chr2-167168093; COSMIC: COSV57601199;