2-166277030-T-G

Variant names:

• chr2-166277030-T-G
• rs12478318
• NM_001365536.1:c.2827A>C

Variant summary

Our verdict is Benign. The variant received -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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M943I) has been classified as Uncertain significance.

• 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
• Publications: 39 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 94089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2827A>C	p.Met943Leu	missense_variant	Exon 16 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2827A>C	p.Met943Leu	missense_variant	Exon 16 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2827A>C	p.Met943Leu	missense_variant	Exon 16 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2794A>C	p.Met932Leu	missense_variant	Exon 16 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2794A>C	p.Met932Leu	missense_variant	Exon 16 of 27			ENSP00000495983.1

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

GnomAD2 exomes AF: 0.0368 AC: 9252 AN: 251290 AF XY: 0.0294

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 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

African (AFR) AF: 0.00191 AC: 64 AN: 33466

American (AMR) AF: 0.192 AC: 8606 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00188 AC: 49 AN: 26132

East Asian (EAS) AF: 0.0508 AC: 2015 AN: 39700

South Asian (SAS) AF: 0.0116 AC: 999 AN: 86254

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53420

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5764

European-Non Finnish (NFE) AF: 0.00242 AC: 2692 AN: 1111942

Other (OTH) AF: 0.0109 AC: 661 AN: 60382

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

African (AFR) AF: 0.00275 AC: 114 AN: 41502

American (AMR) AF: 0.0970 AC: 1481 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.0581 AC: 300 AN: 5166

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4814

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10590

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00338 AC: 230 AN: 67970

Other (OTH) AF: 0.0151 AC: 32 AN: 2116

Alfa AF: 0.00883 Hom.: 117

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

Sep 25, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27956748, 23895530, 25585270, 22803682, 25556685, 25250524, 21698661, 26284228, 27535533, 21939494, 23450472) -

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

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/). -

Primary erythromelalgia Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal extreme pain disorder Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 28, 2023

Gene Friend Way, National Innovation Center

Significance: Uncertain risk allele

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;.
PhyloP100		6.2
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
Mutation Taster		=25/75	polymorphism (auto)

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

Other links and lift over

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