dbSNP rs756969320: PRNP:p.Pro26Pro (chr20-4699298-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_000311.5(PRNP):c.78G>A(p.Pro26Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,006 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PRNP
NM_000311.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.487

Publications

0 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: Genomics England PanelApp, Orphanet, Ambry Genetics
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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
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

PRNP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 20-4699298-G-A is Benign according to our data. Variant chr20-4699298-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2571133.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.487 with no splicing effect.

BS2

High AC in GnomAdExome4 at 31 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000311.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRNP	NM_000311.5	MANE Select	c.78G>A	p.Pro26Pro	synonymous	Exon 2 of 2	NP_000302.1	Q53YK7
PRNP	NM_001080121.3		c.78G>A	p.Pro26Pro	synonymous	Exon 2 of 2	NP_001073590.1	P04156-1
PRNP	NM_001080122.3		c.78G>A	p.Pro26Pro	synonymous	Exon 2 of 2	NP_001073591.1	P04156-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRNP	ENST00000379440.9	TSL:1 MANE Select	c.78G>A	p.Pro26Pro	synonymous	Exon 2 of 2	ENSP00000368752.4	P04156-1
PRNP	ENST00000424424.2	TSL:1	c.78G>A	p.Pro26Pro	synonymous	Exon 2 of 2	ENSP00000411599.2	P04156-1
PRNP	ENST00000430350.2	TSL:1	c.78G>A	p.Pro26Pro	synonymous	Exon 2 of 2	ENSP00000399376.2	P04156-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000360

AC:

AN:

249718

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1112010

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000227

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

2.7

(source)

DANN

Benign

0.67

PhyloP100

-0.49

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over