rs12478318

Positions:

• chr2-166277030-T-G

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.2827A>C​(p.Met943Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0108 in 1,613,876 control chromosomes in the GnomAD database, including 1,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (116 hom., cov: 32)
  • Exomes 𝑓: 0.010 (1120 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 6.19

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=0.0031083524).
• BP6: Variant 2-166277030-T-G is Benign according to our data. Variant chr2-166277030-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 94089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166277030-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2827A>C	p.Met943Leu	missense_variant	16/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.870-58T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2827A>C	p.Met943Leu	missense_variant	16/27		NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1548-58T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2230 AN: 151982 Hom.: 115 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0968

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0579

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0368 AC: 9252 AN: 251290 Hom.: 944 AF XY: 0.0294 AC XY: 3986 AN XY: 135796

Gnomad AFR exome AF: 0.00301

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0595

Gnomad SAS exome AF: 0.0111

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00269

Gnomad OTH exome AF: 0.0246

GnomAD4 exome AF: 0.0103 AC: 15113 AN: 1461776 Hom.: 1120 Cov.: 31 AF XY: 0.00950 AC XY: 6907 AN XY: 727188

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.00188

Gnomad4 EAS exome AF: 0.0508

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00242

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.0147 AC: 2239 AN: 152100 Hom.: 116 Cov.: 32 AF XY: 0.0163 AC XY: 1214 AN XY: 74336

Gnomad4 AFR AF: 0.00275

Gnomad4 AMR AF: 0.0970

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0581

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00338

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00729 Hom.: 66

Bravo AF: 0.0236

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.0295 AC: 3581

Asia WGS AF: 0.0310 AC: 106 AN: 3478

EpiCase AF: 0.00333

EpiControl AF: 0.00225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 25, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 24% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 22. Only high quality variants are reported. -
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. -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2018	This variant is associated with the following publications: (PMID: 27956748, 23895530, 25585270, 22803682, 25556685, 25250524, 21698661, 26284228, 27535533, 21939494, 23450472) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The p.Met932Leu variant in SCN9A has been identified in at least 2 Chinese individuals with partial congenital indifference to pain (PMID: 21939494). This variant is classified as likely benign for partial congenital indifference to pain because it has been identified in >23% of Latino chromosomes and 387 total homozygotes by ExAC (http://gnomad.broadinstitute.org/). -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

Primary erythromelalgia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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

Feb 01, 2024

- -

Paroxysmal extreme pain disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Autism spectrum disorder Other:1

Uncertain risk allele, no assertion criteria provided

clinical testing

Gene Friend Way, National Innovation Center

Jul 28, 2023

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. This variant and other mutations in SCN9A have been found in patients with familial autism (PMID: 27956748). In our study, about 10% of patients diagnosed with ASD carry this SCN9A variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Uncertain	0.53	.;D;.;.;D;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	0.052
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;.;T;T;T;T;T
MetaRNN	Benign	0.0031	T;T;T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	-0.10	.;N;.;.;N;N;.
MutationTaster	Benign	0.00038	P;P;P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N;.;.;.;.;N;.
REVEL	Uncertain	0.57
Sift	Benign	0.31	T;.;.;.;.;T;.
Sift4G	Benign	1.0	T;T;.;.;.;T;.
Vest4		0.70
MutPred		0.65		Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;.;.;
MPC		0.17
ClinPred		0.015	T
GERP RS		5.7
Varity_R		0.54
gMVP		0.73

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: rs12478318; hg19: chr2-167133540; COSMIC: COSV57599687; COSMIC: COSV57599687;