rs1553488759

Positions:

• chr2-166280376-A-ACATTTTTGAATTCCTCAGT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001365536.1(SCN9A):​c.2305_2323dupACTGAGGAATTCAAAAATG​(p.Val775fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN9A NM_001365536.1 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.47

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 12 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 2-166280376-A-ACATTTTTGAATTCCTCAGT is Pathogenic according to our data. Variant chr2-166280376-A-ACATTTTTGAATTCCTCAGT is described in ClinVar as [Pathogenic]. Clinvar id is 471095.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2305_2323dupACTGAGGAATTCAAAAATG	p.Val775fs	frameshift_variant, stop_gained	14/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2305_2323dupACTGAGGAATTCAAAAATG	p.Val775fs	frameshift_variant, stop_gained	14/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2305_2323dupACTGAGGAATTCAAAAATG	p.Val775fs	frameshift_variant, stop_gained	14/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2272_2290dupACTGAGGAATTCAAAAATG	p.Val764fs	frameshift_variant, stop_gained	14/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2272_2290dupACTGAGGAATTCAAAAATG	p.Val764fs	frameshift_variant, stop_gained	14/27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.2272_2290dupACTGAGGAATTCAAAAATG	p.Val764fs	frameshift_variant, stop_gained	14/15	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 11, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val764Aspfs*2) 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 has not been reported in the literature in individuals affected with SCN9A-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 471095). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553488759; hg19: chr2-167136886;