2-166278198-AAACTT-AAACTTAACTT

Variant names:

• chr2-166278198-A-AAACTT
• rs766212849
• NM_001365536.1:c.2454_2458dupAAGTT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001365536.1(SCN9A):​c.2454_2458dupAAGTT​(p.Leu820fs) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN9A NM_001365536.1 frameshift, stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.53
• Publications: 1 publications found

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

Our verdict: Pathogenic. The variant received 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365536.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.2454_2458dupAAGTT	p.Leu820fs	frameshift stop_gained	Exon 15 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.2421_2425dupAAGTT	p.Leu809fs	frameshift stop_gained	Exon 15 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.1029+954_1029+958dupCTTAA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.2454_2458dupAAGTT	p.Leu820fs	frameshift stop_gained	Exon 15 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.2454_2458dupAAGTT	p.Leu820fs	frameshift stop_gained	Exon 15 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.2421_2425dupAAGTT	p.Leu809fs	frameshift stop_gained	Exon 15 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

Splicing

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

Other links and lift over

dbSNP: rs766212849; hg19: chr2-167134708;