chr20-4699752-G-A

Variant names:

• chr20-4699752-G-A
• rs74315403
• NM_000311.5:c.532G>A
• PRNP p.Asp178Asn

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PP3PP5_Strong

The NM_000311.5(PRNP):c.532G>A (p.Asp178Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,876 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003798935: "Published functional studies demonstrate a damaging effect by accelerated misfolding and forming oligomers faster than wild-type protein (Singh et al., 2015);"" and additional evidence is available in ClinVar. This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Fatal familial insomnia (ffi).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 5.94
• Publications: 418 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: Genomics England PanelApp, Ambry Genetics, 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV003798935: "Published functional studies demonstrate a damaging effect by accelerated misfolding and forming oligomers faster than wild-type protein (Singh et al., 2015);"; SCV001386341: Experimental studies have shown that this missense change affects PRNP function (PMID: 9813003, 16313190, 17494694, 23132868, 27350609).; SCV002058395: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 16313190, 23132868).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 1 benign (OR vs. background: 8.3).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PRNP NM_000311.5	MANE Select	c.532G>A p.Asp178Asn	missense	Exon 2 of 2	Prot: NP_000302.1 UniProt:
	PRNP NM_001080121.3		c.532G>A p.Asp178Asn	missense	Exon 2 of 2	Prot: NP_001073590.1 UniProt:
	PRNP NM_001080122.3		c.532G>A p.Asp178Asn	missense	Exon 2 of 2	Prot: NP_001073591.1 UniProt:

PRNP NM_000311.5

MANE Select

HGVSc / HGVSpc.532G>Ap.Asp178Asn

Exon rankExon 2 of 2

missense

Prot: NP_000302.1UniProt: P04156-1Q53YK7

PRNP NM_001080121.3

HGVSc / HGVSpc.532G>Ap.Asp178Asn

Exon rankExon 2 of 2

missense

Prot: NP_001073590.1UniProt: Q53YK7P04156-1

PRNP NM_001080122.3

HGVSc / HGVSpc.532G>Ap.Asp178Asn

Exon rankExon 2 of 2

missense

Prot: NP_001073591.1UniProt: Q53YK7P04156-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PRNP ENST00000379440.9	TSL:1MANE Select	c.532G>A p.Asp178Asn	missense	Exon 2 of 2	Prot: ENSP00000368752.4 UniProt:
	PRNP ENST00000424424.2	TSL:1	c.532G>A p.Asp178Asn	missense	Exon 2 of 2	Prot: ENSP00000411599.2 UniProt:
	PRNP ENST00000430350.2	TSL:1	c.532G>A p.Asp178Asn	missense	Exon 2 of 2	Prot: ENSP00000399376.2 UniProt:

PRNP ENST00000379440.9

TSL:1MANE Select

HGVSc / HGVSpc.532G>Ap.Asp178Asn

Exon rankExon 2 of 2

missense

Prot: ENSP00000368752.4UniProt: P04156

PRNP ENST00000424424.2

TSL:1

HGVSc / HGVSpc.532G>Ap.Asp178Asn

Exon rankExon 2 of 2

missense

Prot: ENSP00000411599.2UniProt: P04156

PRNP ENST00000430350.2

TSL:1

HGVSc / HGVSpc.532G>Ap.Asp178Asn

Exon rankExon 2 of 2

missense

Prot: ENSP00000399376.2UniProt: P04156

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461876	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000327	AC:1	Hom:0	AN:30608	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
2	-	-	Fatal familial insomnia (3)
1	-	-	Gerstmann-Straussler-Scheinker syndrome;C1847650:Spongiform encephalopathy with neuropsychiatric features;C1864112:Huntington disease-like 1 (1)
1	-	-	Huntington disease-like 1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	27
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.90	D
GPN-Star LLR	N/A	-5.4
GPN-Star score	N/A	5.4
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.91	D
Mutation Taster	N/A	6/94	disease causing (ClinVar)
MutationAssessor	Uncertain	2.9	M
PhyloP100	Uncertain	5.9
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.72
VESM-3B	Benign	-7.5

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs74315403;

hg19: chr20-4680398;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar