rs6116474

Positions:

• chr20-4696561-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000379440.9(PRNP):​c.-10-2650T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,126 control chromosomes in the GnomAD database, including 4,122 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4122 hom., cov: 32)
• Consequence: PRNP ENST00000379440.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.428

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRNP	NM_000311.5	c.-10-2650T>C		intron_variant		ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRNP	ENST00000379440.9	c.-10-2650T>C		intron_variant		1	NM_000311.5	ENSP00000368752	P1
PRNP	ENST00000424424.2	c.-5-2655T>C		intron_variant		1		ENSP00000411599	P1
PRNP	ENST00000430350.2	c.-10-2650T>C		intron_variant		1		ENSP00000399376	P1
PRNP	ENST00000457586.2	c.-10-2650T>C		intron_variant		1		ENSP00000415284	P1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34482 AN: 152008 Hom.: 4115 Cov.: 32

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.0202

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.238

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.227 AC: 34527 AN: 152126 Hom.: 4122 Cov.: 32 AF XY: 0.223 AC XY: 16583 AN XY: 74354

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.286

Gnomad4 ASJ AF: 0.238

Gnomad4 EAS AF: 0.0202

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.214

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.236

Alfa AF: 0.250 Hom.: 1264

Bravo AF: 0.232

Asia WGS AF: 0.127 AC: 441 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.5
DANN	Benign	0.58

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: rs6116474; hg19: chr20-4677207;