2-166251875-C-T

Position:

• chr2-166251875-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365536.1(SCN9A):​c.3362G>A​(p.Arg1121Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,611,986 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1121W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (51 hom., cov: 32)
  • Exomes 𝑓: 0.019 (323 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.86

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 (MetaRNN=0.002156794).
• BP6: Variant 2-166251875-C-T is Benign according to our data. Variant chr2-166251875-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166251875-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0219 (3332/151996) while in subpopulation SAS AF= 0.0278 (134/4814). AF 95% confidence interval is 0.0249. There are 51 homozygotes in gnomad4. There are 1752 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 51 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.3362G>A	p.Arg1121Gln	missense_variant	18/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.832C>T		non_coding_transcript_exon_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.3362G>A	p.Arg1121Gln	missense_variant	18/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1510C>T		non_coding_transcript_exon_variant	14/19

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3329 AN: 151878 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0274

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0204 AC: 5064 AN: 247896 Hom.: 80 AF XY: 0.0218 AC XY: 2930 AN XY: 134470

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.00866

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.000224

Gnomad SAS exome AF: 0.0278

Gnomad FIN exome AF: 0.0385

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0188 AC: 27471 AN: 1459990 Hom.: 323 Cov.: 31 AF XY: 0.0193 AC XY: 13983 AN XY: 726258

Gnomad4 AFR exome AF: 0.0289

Gnomad4 AMR exome AF: 0.00898

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0283

Gnomad4 FIN exome AF: 0.0346

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0163

GnomAD4 genome AF: 0.0219 AC: 3332 AN: 151996 Hom.: 51 Cov.: 32 AF XY: 0.0236 AC XY: 1752 AN XY: 74278

Gnomad4 AFR AF: 0.0261

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0278

Gnomad4 FIN AF: 0.0419

Gnomad4 NFE AF: 0.0204

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0182 Hom.: 46

Bravo AF: 0.0196

TwinsUK AF: 0.0167 AC: 62

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.0326 AC: 123

ESP6500EA AF: 0.0195 AC: 160

ExAC AF: 0.0202 AC: 2441

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0177

EpiControl AF: 0.0188

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -

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

Invitae

Feb 01, 2024

- -

Small fiber neuropathy Benign:1

Likely 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
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.3
DANN	Benign	0.60
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.51	T;.;T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.88	N;.;.;.;.;N
REVEL	Benign	0.12
Sift	Benign	0.58	T;.;.;.;.;T
Sift4G	Benign	0.78	T;T;.;.;.;T
Vest4		0.15
MPC		0.14
ClinPred		0.0019	T
GERP RS		-2.9
Varity_R		0.025
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs74401238; hg19: chr2-167108385; COSMIC: COSV104409015;