chr20-4699379-CGGTGGTGGCTGGGGGCAGCCTCAT-C

Position:

chr20-4699379-CGGTGGTGGCTGGGGGCAGCCTCAT-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

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

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.05

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 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.

BS2

High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRNP	NM_000311.5 linkuse as main transcript	c.204_227del	p.Pro84_Gln91del	inframe_deletion	2/2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRNP	ENST00000379440.9 linkuse as main transcript	c.204_227del	p.Pro84_Gln91del	inframe_deletion	2/2	1	NM_000311.5	ENSP00000368752	P1	P04156-1
PRNP	ENST00000424424.2 linkuse as main transcript	c.204_227del	p.Pro84_Gln91del	inframe_deletion	2/2	1		ENSP00000411599	P1	P04156-1
PRNP	ENST00000430350.2 linkuse as main transcript	c.204_227del	p.Pro84_Gln91del	inframe_deletion	2/2	1		ENSP00000399376	P1	P04156-1
PRNP	ENST00000457586.2 linkuse as main transcript	c.204_227del	p.Pro84_Gln91del	inframe_deletion	2/2	1		ENSP00000415284	P1	P04156-1

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

185

AN:

151568

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000541

AC XY:

AN XY:

134918

show subpopulations

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.:

AF XY:

0.000824

AC XY:

599

AN XY:

727070

show subpopulations

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.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74146

show subpopulations

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:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over