NM_001365536.1:c.1828C>A

Variant names:

• chr2-166284599-G-T
• rs41268673
• NM_001365536.1:c.1828C>A

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 (★★).

• 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:18 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 rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1828C>A	p.Pro610Thr	missense_variant	Exon 12 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1828C>A	p.Pro610Thr	missense_variant	Exon 12 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.1828C>A	p.Pro610Thr	missense_variant	Exon 12 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.1828C>A	p.Pro610Thr	missense_variant	Exon 12 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.1828C>A	p.Pro610Thr	missense_variant	Exon 12 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.1828C>A	p.Pro610Thr	missense_variant	Exon 12 of 15	1		ENSP00000413212.2

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:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Apr 30, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 20, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: 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. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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% -

Apr 24, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Primary erythromelalgia Benign:2 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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. -

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

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. -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Inherited Erythromelalgia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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 04, 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. -

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;.
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;