20-4699379-CGGTGGTGGCTGGGGGCAGCCTCAT-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM4 BP6_Very_Strong BS1

The NM_000311.5(PRNP):c.204_227del(p.Pro84_Gln91del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000735 in 1,613,168 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (7 hom.)
• Consequence: PRNP NM_000311.5 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.05

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000311.5.
• BP6: Variant 20-4699379-CGGTGGTGGCTGGGGGCAGCCTCAT-C is Benign according to our data. Variant chr20-4699379-CGGTGGTGGCTGGGGGCAGCCTCAT-C is described in ClinVar as [Likely_benign]. Clinvar id is 65494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699379-CGGTGGTGGCTGGGGGCAGCCTCAT-C is described in Lovd as [Benign]. Variant chr20-4699379-CGGTGGTGGCTGGGGGCAGCCTCAT-C is described in Lovd as [Likely_benign]. Variant chr20-4699379-CGGTGGTGGCTGGGGGCAGCCTCAT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00123 (186/151686) while in subpopulation EAS AF= 0.00351 (18/5134). AF 95% confidence interval is 0.00227. There are 0 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRNP	NM_000311.5	c.204_227del	p.Pro84_Gln91del	inframe_deletion	2/2	ENST00000379440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRNP	ENST00000379440.9	c.204_227del	p.Pro84_Gln91del	inframe_deletion	2/2	1	NM_000311.5	P1
PRNP	ENST00000424424.2	c.204_227del	p.Pro84_Gln91del	inframe_deletion	2/2	1		P1
PRNP	ENST00000430350.2	c.204_227del	p.Pro84_Gln91del	inframe_deletion	2/2	1		P1
PRNP	ENST00000457586.2	c.204_227del	p.Pro84_Gln91del	inframe_deletion	2/2	1		P1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 151568 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00350

Gnomad SAS AF: 0.00230

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000528 AC: 131 AN: 248054 Hom.: 0 AF XY: 0.000541 AC XY: 73 AN XY: 134918

Gnomad AFR exome AF: 0.000263

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00104

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000684 AC: 999 AN: 1461482 Hom.: 7 AF XY: 0.000824 AC XY: 599 AN XY: 727070

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00171

Gnomad4 SAS exome AF: 0.00365

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.000395

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00123 AC: 186 AN: 151686 Hom.: 0 Cov.: 32 AF XY: 0.00116 AC XY: 86 AN XY: 74146

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00351

Gnomad4 SAS AF: 0.00231

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.000475

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	PRNP: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2021	This variant is associated with the following publications: (PMID: 16914329, 18455951, 22717776) -

Gerstmann-Straussler-Scheinker syndrome;C0206042:Fatal familial insomnia;C0751254:Inherited Creutzfeldt-Jakob disease;C1847650:Spongiform encephalopathy with neuropsychiatric features;C1855588:Kuru, susceptibility to;C1864112:Huntington disease-like 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 26, 2021

- -

Inherited prion disease Benign:1

Benign, no assertion criteria provided

curation

GeneReviews

Dec 18, 2008

- -

Huntington disease-like 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922906; hg19: chr20-4680025;