rs74315406

Variant names:

• chr20-4699870-A-G
• rs74315406
• NM_000311.5:c.650A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000311.5(PRNP):​c.650A>G​(p.Gln217Arg) variant causes a missense change. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.84
• Publications: 57 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000311.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 20-4699870-A-G is Pathogenic according to our data. Variant chr20-4699870-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 13402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRNP	NM_000311.5	MANE Select	c.650A>G	p.Gln217Arg	missense	Exon 2 of 2	NP_000302.1
	PRNP	NM_001080121.3		c.650A>G	p.Gln217Arg	missense	Exon 2 of 2	NP_001073590.1
	PRNP	NM_001080122.3		c.650A>G	p.Gln217Arg	missense	Exon 2 of 2	NP_001073591.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRNP	ENST00000379440.9	TSL:1 MANE Select	c.650A>G	p.Gln217Arg	missense	Exon 2 of 2	ENSP00000368752.4
	PRNP	ENST00000424424.2	TSL:1	c.650A>G	p.Gln217Arg	missense	Exon 2 of 2	ENSP00000411599.2
	PRNP	ENST00000430350.2	TSL:1	c.650A>G	p.Gln217Arg	missense	Exon 2 of 2	ENSP00000399376.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Gerstmann-Straussler-Scheinker syndrome (1)
1	-	-	Huntington disease-like 1 (1)
1	-	-	PRNP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.8
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.87
MutPred		0.92		Gain of solvent accessibility (P = 0.0584)
MVP		1.0
MPC		0.76
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.78
gMVP		0.98
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs74315406; hg19: chr20-4680516;