rs180922748

chr2-166233432-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5 BP4_Strong BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:11
• Conservation: PhyloP100: 2.27

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 Likely_benign. Variant got -3 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].

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 151970 Hom.: 1 Cov.: 31

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.: 0 AF XY: 0.00125 AC XY: 146 AN XY: 117104

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.: 8 Cov.: 29 AF XY: 0.00206 AC XY: 1456 AN XY: 707200

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.: 1 Cov.: 31 AF XY: 0.00172 AC XY: 128 AN XY: 74354

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.: 1

Bravo AF: 0.00184

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000529 AC: 2

ESP6500EA AF: 0.00229 AC: 19

ExAC AF: 0.00129 AC: 156

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:3

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. -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SCN9A: BS1 -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Invitae

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	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;.;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.031	T;T;T;T;T
MetaSVM	Pathogenic	0.87	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
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	T
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

Other links and lift over

dbSNP: rs180922748; hg19: chr2-167089942; COSMIC: COSV104409284;