rs1553473041

Positions:

• chr2-166199287-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001365536.1(SCN9A):​c.5351delA​(p.Glu1784fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN9A NM_001365536.1 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.93

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:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.103 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-166199287-CT-C is Pathogenic according to our data. Variant chr2-166199287-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 471143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.5351delA	p.Glu1784fs	frameshift_variant	27/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.5351delA	p.Glu1784fs	frameshift_variant	27/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.5351delA	p.Glu1784fs	frameshift_variant	27/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.5318delA	p.Glu1773fs	frameshift_variant	27/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.5318delA	p.Glu1773fs	frameshift_variant	27/27			ENSP00000495983.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000226 AC: 33 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727248

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: 0.0000297

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2023

The c.5318delA (p.E1773Gfs*14) alteration, located in exon 27 (coding exon 26) of the SCN9A gene, consists of a deletion of one nucleotide at position 5318, causing a translational frameshift with a predicted alternate stop codon after 14 amino acids. This alteration occurs at the 3' terminus of the SCN9A gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 10.4% of the protein. Premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). _x000D_ _x000D_ Based on the available evidence, the SCN9A c.5318delA (p.E1773Gfs*14) alteration is classified as likely pathogenic for autosomal recessive congenital insensitivity to pain; however, its clinical significance for autosomal dominant SCN9A-related neuropathic pain syndromes is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported compound heterozygous with c.2488C>T (p.R830*) in an individual with congenital insensitivity to pain and anosmia (Ramirez, 2014; McDermott, 2019) . An in vitro functional analysis of this variant has shown a significant reduction in protein function compared to wild-type (McDermott, 2019). Based on the available evidence, this alteration is classified as likely pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0604 - There is no annotated protein domain located downstream of this variant (DECIPHER). (I) 0708 - Other premature termination variants (PTVs) comparable to the one identified in this case have conflicting previous evidence for pathogenicity. PTVs located downstream of this variant had been reported in individuals with congenital insensitivity to pain (PMIDs: 28494607, 25995458), and as likely pathogenic or uncertain significance in ClinVar. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It has been reported in two affected siblings as compound heterozygous with an NMD-predicted variant (PMID: 25253744). It has also been reported as pathogenic once in ClinVar. (SP) 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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects SCN9A function (PMID: 30795902). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 471143). This premature translational stop signal has been observed in individual(s) with congenital insensitivity to pain (PMID: 25253744). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1773Glyfs*14) in the SCN9A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 205 amino acid(s) of the SCN9A protein. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 22, 2023

Published functional studies demonstrate significantly reduced current density of the channel resulting in almost complete loss of channel function (McDermott et al., 2019); Frameshift variant predicted to result in protein truncation, as the last 205 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25253744, 30795902) -

Computational scores

Source: dbNSFP v4.3

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: rs1553473041; hg19: chr2-167055797;