rs121908919

Positions:

• chr2-166281786-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001365536.1(SCN9A):​c.1997A>G​(p.Lys666Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,612,600 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:17
• Conservation: PhyloP100: 0.413

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035237223).
• BP6: Variant 2-166281786-T-C is Benign according to our data. Variant chr2-166281786-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 6367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166281786-T-C is described in Lovd as [Pathogenic]. Variant chr2-166281786-T-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1997A>G	p.Lys666Arg	missense_variant	13/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.1029+4539T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1997A>G	p.Lys666Arg	missense_variant	13/27		NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1707+4539T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 264 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00195 AC: 483 AN: 247652 Hom.: 1 AF XY: 0.00188 AC XY: 252 AN XY: 134370

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.00300

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000660

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00298

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00238 AC: 3480 AN: 1460440 Hom.: 5 Cov.: 30 AF XY: 0.00228 AC XY: 1656 AN XY: 726462

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00287

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000930

Gnomad4 FIN exome AF: 0.00141

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00174 AC: 264 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74378

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00263

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00233 Hom.: 1

Bravo AF: 0.00181

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00231 AC: 19

ExAC AF: 0.00189 AC: 228

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00322

EpiControl AF: 0.00327

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:8

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Likely 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2021	This variant is associated with the following publications: (PMID: 24717127, 22604722, 27504264, 23129781, 19763161, 25250524, 27582484, 27916648, 26264438, 29176367, 30642272, 30478917, 31372899) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SCN9A: BP4, BS2 -

Generalized epilepsy with febrile seizures plus, type 7 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -

Primary erythromelalgia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
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. -

Hypoglycemia;C0036572:Seizure;C0557874:Global developmental delay Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 15, 2014

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

SCN9A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	13
DANN	Benign	0.53
DEOGEN2	Benign	0.21	.;T;.;.;T;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.65	T;.;T;T;T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.035	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	-0.42	.;N;.;.;N;N;.
MutationTaster	Benign	0.51	A;A;A;A
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.16	N;.;.;.;.;N;.
REVEL	Uncertain	0.52
Sift	Benign	1.0	T;.;.;.;.;T;.
Sift4G	Benign	0.41	T;T;.;.;.;T;.
Polyphen		0.0030	.;B;.;.;B;.;.
Vest4		0.40
MVP		0.65
MPC		0.096
ClinPred		0.0023	T
GERP RS		4.5
Varity_R		0.054
gMVP		0.41

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: rs121908919; hg19: chr2-167138296;