rs180922748

Positions:

chr2-166233432-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5BP4_StrongBP6BS2

The NM_001365536.1(SCN9A):c.3832C>G(p.Leu1278Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,576,608 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1278I) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0021 ( 8 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:11

Conservation

PhyloP100: 2.27

Variant links:

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]

SCN9A links:

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

SCN1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-166233432-G-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.031454235).

BP6

Variant 2-166233432-G-C is Benign according to our data. Variant chr2-166233432-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195592.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Uncertain_significance=1}. Variant chr2-166233432-G-C is described in Lovd as [Pathogenic].

BS2

High Homozygotes in GnomAdExome4 at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.3832C>G	p.Leu1278Val	missense_variant	21/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1 linkuse as main transcript	n.612-14763G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2 linkuse as main transcript	c.3832C>G	p.Leu1278Val	missense_variant	21/27		NM_001365536.1	ENSP00000495601	P1	Q15858-1
SCN1A-AS1	ENST00000651574.1 linkuse as main transcript	n.1290-14763G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00171

AC:

260

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00289

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00122

AC:

261

AN:

214484

Hom.:

AF XY:

0.00125

AC XY:

146

AN XY:

117104

show subpopulations

Gnomad AFR exome

AF:

0.000451

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000427

Gnomad NFE exome

AF:

0.00207

Gnomad OTH exome

AF:

0.000795

GnomAD4 exome

AF:

0.00214

AC:

3052

AN:

1424522

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

1456

AN XY:

707200

show subpopulations

Gnomad4 AFR exome

AF:

0.000193

Gnomad4 AMR exome

AF:

0.00133

Gnomad4 ASJ exome

AF:

0.0000791

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000130

Gnomad4 FIN exome

AF:

0.000584

Gnomad4 NFE exome

AF:

0.00257

Gnomad4 OTH exome

AF:

0.00217

GnomAD4 genome

AF:

0.00171

AC:

260

AN:

152086

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000944

Gnomad4 NFE

AF:

0.00289

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00224

Hom.:

Bravo

AF:

0.00184

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000529

AC:

ESP6500EA

AF:

0.00229

AC:

ExAC

AF:

0.00129

AC:

156

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SCN9A: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 25, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2021	This variant is associated with the following publications: (PMID: 28440294, 23895530, 24776970, 24848745, 19763161, 25250524, 26284228, 29176367) -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2022	The SCN9A c.3799C>G; p.Leu1267Val variant (rs180922748) is reported in the literature in two patients with Dravet syndrome (Mulley 2013, Singh 2009). However, both individuals also carried a clearly pathogenic variant in a different gene associated with Dravet or similar seizure disorder. This variant was also reported in a case with diabetic peripheral neuropathy; however, the patient carried an additional variant in SCN11A (Blesneac 2018). This variant is reported in ClinVar (Variation ID: 195592) and is found in the non-Finnish European population with an allele frequency of 0.22% (261/117658 alleles) in the Genome Aggregation Database. The leucine at codon 1267 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.766). However, given the lack of clinical and functional data, the significance of the p.Leu1267Val variant is uncertain at this time. References: Blesneac I et al. Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy. Pain. 2018 Mar;159(3):469-480. PMID: 29176367. Mulley et al. Role of the sodium channel SCN9A in genetic epilepsy with febrile seizures plus and Dravet syndrome. Epilepsia. 2013; 54(9): e122-6. PMID: 23895530. Singh et al. A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genet. 2009; 5(9): e1000649. PMID: 19763161. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 31, 2023	Variant summary: SCN9A c.3799C>G (p.Leu1267Val) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 214484 control chromosomes. This frequency does not allow conclusions about variant significance. Although appearing in the literature, to our knowledge, no penetrant association of c.3799C>G in individuals affected with SCN9A-related disorders such as Primary Erythermalgia/Hereditary Sensory Neuropathy type IID/Congenital insensitivity to pain and no conclusive experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another known variant in the GABRG2 gene in an individual reportedly affected with Dravet syndrome has been ascertained, providing supporting evidence for a benign role (Mulley_SCN9A_Epilepsia_2013). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as likely benign (n=7). Based on the evidence outlined above, the variant was classified as likely benign. -

Childhood epilepsy with centrotemporal spikes

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Inherited Erythromelalgia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Primary erythromelalgia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2022

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

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Paroxysmal extreme pain disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

.;D;.;D;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;.;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.031

T;T;T;T;T

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.4

.;M;.;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.6

D;.;.;.;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

D;.;.;.;D

Sift4G

Benign

0.077

T;T;.;.;T

Vest4

0.39

MVP

0.87

MPC

0.46

ClinPred

0.15

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.66

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over