2-166238220-G-T

Position:

• chr2-166238220-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001365536.1(SCN9A):​c.3675C>A​(p.Ile1225Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,600,150 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (48 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.750

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:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-166238220-G-T is Benign according to our data. Variant chr2-166238220-G-T is described in ClinVar as [Benign]. Clinvar id is 130264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166238220-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00207 (315/152046) while in subpopulation EAS AF= 0.0505 (261/5164). AF 95% confidence interval is 0.0455. There are 4 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3675C>A	p.Ile1225Ile	synonymous_variant	20/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3675C>A	p.Ile1225Ile	synonymous_variant	20/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.3675C>A	p.Ile1225Ile	synonymous_variant	20/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.3642C>A	p.Ile1214Ile	synonymous_variant	20/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.3642C>A	p.Ile1214Ile	synonymous_variant	20/27			ENSP00000495983.1

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 151928 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0508

Gnomad SAS AF: 0.00457

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00426 AC: 996 AN: 233756 Hom.: 22 AF XY: 0.00413 AC XY: 522 AN XY: 126290

Gnomad AFR exome AF: 0.000341

Gnomad AMR exome AF: 0.0000941

Gnomad ASJ exome AF: 0.000514

Gnomad EAS exome AF: 0.0501

Gnomad SAS exome AF: 0.00178

Gnomad FIN exome AF: 0.000898

Gnomad NFE exome AF: 0.000312

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00148 AC: 2144 AN: 1448104 Hom.: 48 Cov.: 28 AF XY: 0.00148 AC XY: 1064 AN XY: 719562

Gnomad4 AFR exome AF: 0.000181

Gnomad4 AMR exome AF: 0.0000928

Gnomad4 ASJ exome AF: 0.000425

Gnomad4 EAS exome AF: 0.0406

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.000829

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.00359

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152046 Hom.: 4 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74314

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0505

Gnomad4 SAS AF: 0.00499

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.00244

Asia WGS AF: 0.0270 AC: 93 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Eurofins Ntd Llc (ga)	Mar 19, 2015	- -

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. -

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

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Small fiber neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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	-0.45
CADD	Benign	3.7
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs77144869; hg19: chr2-167094730; COSMIC: COSV57611133; COSMIC: COSV57611133;