2-166226650-C-T

Variant names:

• chr2-166226650-C-T
• rs149346064
• NM_001365536.1:c.4315G>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.4315G>A​(p.Val1439Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000978 in 1,589,422 control chromosomes in the GnomAD database, including 14 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 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (12 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.43

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=0.010564268).
• BP6: Variant 2-166226650-C-T is Benign according to our data. Variant chr2-166226650-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 287829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166226650-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000966 (1388/1437348) while in subpopulation MID AF= 0.0121 (69/5724). AF 95% confidence interval is 0.00977. There are 12 homozygotes in gnomad4_exome. There are 774 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.4315G>A	p.Val1439Ile	missense_variant	Exon 24 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.4315G>A	p.Val1439Ile	missense_variant	Exon 24 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.4315G>A	p.Val1439Ile	missense_variant	Exon 24 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.4282G>A	p.Val1428Ile	missense_variant	Exon 24 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.4282G>A	p.Val1428Ile	missense_variant	Exon 24 of 27			ENSP00000495983.1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 151958 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000633

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00161 AC: 369 AN: 228762 Hom.: 6 AF XY: 0.00171 AC XY: 211 AN XY: 123646

Gnomad AFR exome AF: 0.000215

Gnomad AMR exome AF: 0.000605

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.000117

Gnomad SAS exome AF: 0.00318

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000594

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.000966 AC: 1388 AN: 1437348 Hom.: 12 Cov.: 28 AF XY: 0.00109 AC XY: 774 AN XY: 712992

Gnomad4 AFR exome AF: 0.000122

Gnomad4 AMR exome AF: 0.000590

Gnomad4 ASJ exome AF: 0.0195

Gnomad4 EAS exome AF: 0.000231

Gnomad4 SAS exome AF: 0.00313

Gnomad4 FIN exome AF: 0.0000380

Gnomad4 NFE exome AF: 0.000381

Gnomad4 OTH exome AF: 0.00188

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152074 Hom.: 2 Cov.: 32 AF XY: 0.00108 AC XY: 80 AN XY: 74336

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00374

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000633

Gnomad4 OTH AF: 0.00333

Alfa AF: 0.00200 Hom.: 0

Bravo AF: 0.000994

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000240 AC: 1

ESP6500EA AF: 0.000825 AC: 7

ExAC AF: 0.00136 AC: 164

Asia WGS AF: 0.00174 AC: 6 AN: 3466

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN9A: BS2 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 27, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26989088, 28235406, 32707200) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

Feb 11, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 25, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary erythromelalgia Benign:1

Jan 13, 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. -

Inborn genetic diseases Benign:1

Jan 13, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Small fiber neuropathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal extreme pain disorder Benign:1

Jan 13, 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	0.056
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	16
DANN	Benign	0.60
DEOGEN2	Uncertain	0.43	.;T;.;.;T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.32	T;.;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.011	T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	-0.88	.;N;.;.;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.37	N;N;.;.;.;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T;D;.;.;.;T
Sift4G	Benign	1.0	T;T;.;.;.;T
Vest4		0.28
MVP		0.34
MPC		0.093
ClinPred		0.0045	T
GERP RS		4.3
Varity_R		0.058
gMVP		0.31

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: rs149346064; hg19: chr2-167083160; COSMIC: COSV57610858;