rs62643364

Positions:

• chr20-4699466-A-G
• chr20-4699466-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000311.5(PRNP):​c.246A>G​(p.Gly82=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000937 in 1,569,202 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000081 (1 hom.)
• Consequence: PRNP NM_000311.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.27

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 20-4699466-A-G is Benign according to our data. Variant chr20-4699466-A-G is described in ClinVar as [Benign]. Clinvar id is 338648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.27 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRNP	NM_000311.5	c.246A>G	p.Gly82=	synonymous_variant	2/2	ENST00000379440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRNP	ENST00000379440.9	c.246A>G	p.Gly82=	synonymous_variant	2/2	1	NM_000311.5	P1
PRNP	ENST00000424424.2	c.246A>G	p.Gly82=	synonymous_variant	2/2	1		P1
PRNP	ENST00000430350.2	c.246A>G	p.Gly82=	synonymous_variant	2/2	1		P1
PRNP	ENST00000457586.2	c.246A>G	p.Gly82=	synonymous_variant	2/2	1		P1

Frequencies

GnomAD3 genomes AF: 0.000229 AC: 31 AN: 135606 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000573

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000493

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000589

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000747

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000145 AC: 36 AN: 248842 Hom.: 1 AF XY: 0.000119 AC XY: 16 AN XY: 134932

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000809 AC: 116 AN: 1433514 Hom.: 1 Cov.: 31 AF XY: 0.0000938 AC XY: 67 AN XY: 714164

Gnomad4 AFR exome AF: 0.000357

Gnomad4 AMR exome AF: 0.0000932

Gnomad4 ASJ exome AF: 0.0000394

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000815

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.0000672

Gnomad4 OTH exome AF: 0.000189

GnomAD4 genome AF: 0.000228 AC: 31 AN: 135688 Hom.: 0 Cov.: 31 AF XY: 0.000210 AC XY: 14 AN XY: 66556

Gnomad4 AFR AF: 0.000572

Gnomad4 AMR AF: 0.000492

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000591

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000747

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0165 Hom.: 66

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inherited prion disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Huntington disease-like 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.069
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs62643364; hg19: chr20-4680112; COSMIC: COSV65174158;