rs367543047

Positions:

• chr20-4699373-T-TCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAG
• chr20-4699373-T-TCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAG
• chr20-4699373-T-TCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAG
• chr20-4699373-T-TCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAG
• chr20-4699373-T-TCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAG
• chr20-4699373-T-TCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAG
• chr20-4699373-T-TCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAG
• chr20-4699373-T-TCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_000311.5(PRNP):​c.178_179insAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGC​(p.Gln59_Pro60insGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGln) variant causes a disruptive inframe insertion 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRNP NM_000311.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31

Genes affected

PRNP (HGNC:9449): (prion protein (Kanno blood group)) The protein encoded by this gene is a membrane glycosylphosphatidylinositol-anchored glycoprotein that tends to aggregate into rod-like structures. The encoded protein contains a highly unstable region of five tandem octapeptide repeats. This gene is found on chromosome 20, approximately 20 kbp upstream of a gene which encodes a biochemically and structurally similar protein to the one encoded by this gene. Mutations in the repeat region as well as elsewhere in this gene have been associated with Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Straussler disease, Huntington disease-like 1, and kuru. An overlapping open reading frame has been found for this gene that encodes a smaller, structurally unrelated protein, AltPrp. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000311.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRNP	NM_000311.5	c.178_179insAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGC	p.Gln59_Pro60insGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGln	disruptive_inframe_insertion	2/2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRNP	ENST00000379440.9	c.178_179insAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGC	p.Gln59_Pro60insGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGln	disruptive_inframe_insertion	2/2	1	NM_000311.5	ENSP00000368752.4
PRNP	ENST00000424424.2	c.178_179insAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGC	p.Gln59_Pro60insGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGln	disruptive_inframe_insertion	2/2	1		ENSP00000411599.2
PRNP	ENST00000430350.2	c.178_179insAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGC	p.Gln59_Pro60insGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGln	disruptive_inframe_insertion	2/2	1		ENSP00000399376.2
PRNP	ENST00000457586.2	c.178_179insAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGCAGGGCGGTGGTGGCTGGGGGCAGC	p.Gln59_Pro60insGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGlnGlnGlyGlyGlyGlyTrpGlyGln	disruptive_inframe_insertion	2/2	1		ENSP00000415284.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

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: rs367543047; hg19: chr20-4680019;