20-4699899-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_000311.5(PRNP):​c.679C>T​(p.Gln227*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

PRNP
NM_000311.5 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.768
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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 0.109 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 20-4699899-C-T is Pathogenic according to our data. Variant chr20-4699899-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 88927.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRNPNM_000311.5 linkc.679C>T p.Gln227* stop_gained 2/2 ENST00000379440.9 NP_000302.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRNPENST00000379440.9 linkc.679C>T p.Gln227* stop_gained 2/21 NM_000311.5 ENSP00000368752.4 P04156-1
PRNPENST00000424424.2 linkc.679C>T p.Gln227* stop_gained 2/21 ENSP00000411599.2 P04156-1A2A2V1
PRNPENST00000430350.2 linkc.679C>T p.Gln227* stop_gained 2/21 ENSP00000399376.2 P04156-1
PRNPENST00000457586.2 linkc.679C>T p.Gln227* stop_gained 2/21 ENSP00000415284.2 P04156-1X6RKS3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Gerstmann-Straussler-Scheinker syndrome Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2010- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
34
DANN
Benign
0.95
Eigen
Uncertain
0.20
Eigen_PC
Benign
-0.17
FATHMM_MKL
Benign
0.12
N
Vest4
0.84
GERP RS
1.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs17852079; hg19: chr20-4680545; API