NM_000311.5:c.-245C>G

Variant names:

• chr20-4686278-C-G
• rs13040327
• NM_000311.5:c.-245C>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000311.5(PRNP):​c.-245C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0878 in 152,270 control chromosomes in the GnomAD database, including 874 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (873 hom., cov: 32)
  • Exomes 𝑓: 0.11 (1 hom.)
• Consequence: PRNP NM_000311.5 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.89

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 20-4686278-C-G is Benign according to our data. Variant chr20-4686278-C-G is described in ClinVar as [Benign]. Clinvar id is 338639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRNP	NM_000311.5	c.-245C>G		upstream_gene_variant		ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRNP	ENST00000379440.9	c.-245C>G		upstream_gene_variant		1	NM_000311.5	ENSP00000368752.4
PRNP	ENST00000424424.2	c.-240C>G		upstream_gene_variant		1		ENSP00000411599.2
PRNP	ENST00000430350.2	c.-241C>G		upstream_gene_variant		1		ENSP00000399376.2

Frequencies

GnomAD3 genomes AF: 0.0879 AC: 13366 AN: 152088 Hom.: 871 Cov.: 32

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.0630

Gnomad ASJ AF: 0.0629

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0225

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.0857

GnomAD4 exome AF: 0.109 AC: 7 AN: 64 Hom.: 1 Cov.: 0 AF XY: 0.0962 AC XY: 5 AN XY: 52

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0878 AC: 13367 AN: 152206 Hom.: 873 Cov.: 32 AF XY: 0.0870 AC XY: 6476 AN XY: 74396

Gnomad4 AFR AF: 0.0228

Gnomad4 AMR AF: 0.0629

Gnomad4 ASJ AF: 0.0629

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.0848

Alfa AF: 0.115 Hom.: 151

Bravo AF: 0.0758

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inherited prion disease Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.81

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: rs13040327; hg19: chr20-4666924;