NM_000311.5:c.198G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP7BS2

The NM_000311.5(PRNP):​c.198G>A​(p.Gly66Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

PRNP
NM_000311.5 synonymous

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -5.68

Publications

1 publications found
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]
PRNP Gene-Disease associations (from GenCC):
  • Gerstmann-Straussler-Scheinker syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
  • Huntington disease-like 1
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
  • inherited Creutzfeldt-Jakob disease
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • familial Alzheimer-like prion disease
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • fatal familial insomnia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • PrP systemic amyloidosis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.93).
BP7
Synonymous conserved (PhyloP=-5.68 with no splicing effect.
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRNPNM_000311.5 linkc.198G>A p.Gly66Gly synonymous_variant Exon 2 of 2 ENST00000379440.9 NP_000302.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRNPENST00000379440.9 linkc.198G>A p.Gly66Gly synonymous_variant Exon 2 of 2 1 NM_000311.5 ENSP00000368752.4 P04156-1
PRNPENST00000424424.2 linkc.198G>A p.Gly66Gly synonymous_variant Exon 2 of 2 1 ENSP00000411599.2 P04156-1A2A2V1
PRNPENST00000430350.2 linkc.198G>A p.Gly66Gly synonymous_variant Exon 2 of 2 1 ENSP00000399376.2 P04156-1
PRNPENST00000457586.2 linkc.198G>A p.Gly66Gly synonymous_variant Exon 2 of 2 1 ENSP00000415284.2 P04156-1X6RKS3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000406
AC:
1
AN:
246494
AF XY:
0.00000746
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000548
AC:
8
AN:
1460692
Hom.:
0
Cov.:
31
AF XY:
0.00000826
AC XY:
6
AN XY:
726648
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33402
American (AMR)
AF:
0.00
AC:
0
AN:
44690
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26118
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39682
South Asian (SAS)
AF:
0.0000928
AC:
8
AN:
86170
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53200
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5492
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111640
Other (OTH)
AF:
0.00
AC:
0
AN:
60298
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000361
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Spongiform encephalopathy with neuropsychiatric features Uncertain:1
Jun 26, 2016
Undiagnosed Diseases Network, NIH
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.93
CADD
Benign
0.066
DANN
Benign
0.37
PhyloP100
-5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs750069679; hg19: chr20-4680064; API