chr2-166278233-C-T

Variant names:

• chr2-166278233-C-T
• rs769971743
• NM_001365536.1:c.2424G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001365536.1(SCN9A):​c.2424G>A​(p.Trp808*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,460,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SCN9A NM_001365536.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-166278233-C-T is Pathogenic according to our data. Variant chr2-166278233-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 573007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2424G>A	p.Trp808*	stop_gained	Exon 15 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2424G>A	p.Trp808*	stop_gained	Exon 15 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2424G>A	p.Trp808*	stop_gained	Exon 15 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2391G>A	p.Trp797*	stop_gained	Exon 15 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2391G>A	p.Trp797*	stop_gained	Exon 15 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.2391G>A	p.Trp797*	stop_gained	Exon 15 of 15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247772 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460206 Hom.: 0 Cov.: 30 AF XY: 0.00000964 AC XY: 7 AN XY: 726414

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000120 Hom.: 0

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Dec 18, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2391G>A (p.W797*) alteration, located in exon 15 (coding exon 14) of the SCN9A gene, consists of a G to A substitution at nucleotide position 2391. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 797. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the available evidence, the SCN9A c.2391G>A (p.W797*) alteration is classified as pathogenic for autosomal recessive congenital insensitivity to pain; however, its clinical significance for autosomal dominant SCN9A-related neuropathic pain syndromes is unclear. Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/247772) total alleles studied. The highest observed frequency was 0.001% (1/112376) of European (non-Finnish) alleles. Based on the available evidence, this alteration is classified as pathogenic. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Pathogenic:1

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

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 Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function variants are associated with congenital insensitivity to pain (MIM#243000); gain of function variants are associated with primary erythermalgia (MIM#133020) and paroxysmal extreme pain disorder (MIM#167400) (PMID: 18060017). (I) 0108 - This gene is associated with both recessive and dominant disease. Type IID hereditary sensory and autonomic neuropathy, and congenital insensitivity to pain (MIM#243000) are associated with autosomal recessive inheritance; primary erythermalgia and small fiber neuropathy (MIM#133020), and paroxysmal extreme pain disorder (MIM#167400) are inherited in an autosomal dominant pattern (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Small fiber neuropathy is associated with reduced penetrance (PMID: 20301342). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as likely pathogenic/pathogenic (ClinVar), and are associated with autosomal recessive congenital insensitivity to pain (PMID: 18060017). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It has been reported as pathogenic once in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp797*) in the SCN9A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN9A are known to be pathogenic (PMID: 17470132, 19304393). This variant is present in population databases (rs769971743, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. ClinVar contains an entry for this variant (Variation ID: 573007). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.88
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs769971743; hg19: chr2-167134743;