2-166284599-G-T

Position:

• chr2-166284599-G-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.1828C>A​(p.Pro610Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,614,034 control chromosomes in the GnomAD database, including 674 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. P610A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (49 hom., cov: 32)
  • Exomes 𝑓: 0.027 (625 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 2.17

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=0.027049392).
• BP6: Variant 2-166284599-G-T is Benign according to our data. Variant chr2-166284599-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 21344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166284599-G-T is described in Lovd as [Benign]. Variant chr2-166284599-G-T is described in Lovd as [Likely_benign]. Variant chr2-166284599-G-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0208 (3171/152292) while in subpopulation NFE AF= 0.0305 (2074/68024). AF 95% confidence interval is 0.0294. There are 49 homozygotes in gnomad4. There are 1504 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.1828C>A	p.Pro610Thr	missense_variant	12/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.1029+7352G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.1828C>A	p.Pro610Thr	missense_variant	12/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1707+7352G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3175 AN: 152174 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0720

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.0244

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0305

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0240 AC: 5982 AN: 249200 Hom.: 122 AF XY: 0.0251 AC XY: 3392 AN XY: 135186

Gnomad AFR exome AF: 0.00426

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.0685

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0139

Gnomad FIN exome AF: 0.0263

Gnomad NFE exome AF: 0.0318

Gnomad OTH exome AF: 0.0304

GnomAD4 exome AF: 0.0266 AC: 38871 AN: 1461742 Hom.: 625 Cov.: 32 AF XY: 0.0268 AC XY: 19455 AN XY: 727156

Gnomad4 AFR exome AF: 0.00382

Gnomad4 AMR exome AF: 0.0138

Gnomad4 ASJ exome AF: 0.0709

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.0263

Gnomad4 NFE exome AF: 0.0286

Gnomad4 OTH exome AF: 0.0267

GnomAD4 genome AF: 0.0208 AC: 3171 AN: 152292 Hom.: 49 Cov.: 32 AF XY: 0.0202 AC XY: 1504 AN XY: 74480

Gnomad4 AFR AF: 0.00436

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0720

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0155

Gnomad4 FIN AF: 0.0244

Gnomad4 NFE AF: 0.0305

Gnomad4 OTH AF: 0.0198

Alfa AF: 0.0285 Hom.: 133

Bravo AF: 0.0194

TwinsUK AF: 0.0307 AC: 114

ALSPAC AF: 0.0283 AC: 109

ESP6500AA AF: 0.00554 AC: 24

ESP6500EA AF: 0.0294 AC: 251

ExAC AF: 0.0239 AC: 2904

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0357

EpiControl AF: 0.0354

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP(all): 275/12878= 2.1% -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 30, 2014	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 14, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Primary erythromelalgia Benign:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 3.096% (rs41268673, 4,055/128,392 alleles, 75 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.4.0, this variant is classified as BENIGN. Following criteria are met: BA1 -
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. -

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

Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of insensitivity to pain, congenital (MIM#243000), with 50 homozygotes in gnomAD v3. (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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. -

Inherited Erythromelalgia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

- -

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	0.080
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.27	.;T;.;.;T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.86	D;.;D;D;D;D;D
MetaRNN	Benign	0.027	T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	2.0	M;M;M;.;M;M;.
MutationTaster	Benign	4.6e-8	A;A;A;A
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.77	N;N;.;.;.;N;.
REVEL	Uncertain	0.33
Sift	Benign	0.076	T;T;.;.;.;T;.
Sift4G	Benign	0.31	T;T;.;.;.;T;.
Polyphen		0.0010	.;B;.;.;B;.;.
Vest4		0.26
MPC		0.14
ClinPred		0.0039	T
GERP RS		2.6
Varity_R		0.052
gMVP		0.65

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: rs41268673; hg19: chr2-167141109; COSMIC: COSV57609613; COSMIC: COSV57609613;