rs398122370

Positions:

• chr20-4699851-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000311.5(PRNP):​c.631G>C​(p.Glu211Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E211D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.22

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000311.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 20-4699851-G-C is Pathogenic according to our data. Variant chr20-4699851-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 88923.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-4699851-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRNP	NM_000311.5	c.631G>C	p.Glu211Gln	missense_variant	2/2	ENST00000379440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRNP	ENST00000379440.9	c.631G>C	p.Glu211Gln	missense_variant	2/2	1	NM_000311.5	P1
PRNP	ENST00000424424.2	c.631G>C	p.Glu211Gln	missense_variant	2/2	1		P1
PRNP	ENST00000430350.2	c.631G>C	p.Glu211Gln	missense_variant	2/2	1		P1
PRNP	ENST00000457586.2	c.631G>C	p.Glu211Gln	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Inherited Creutzfeldt-Jakob disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	.;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	2.0	M;M;.;.
MutationTaster	Benign	0.92	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.44	N;N;N;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.71
MutPred		0.86		Gain of MoRF binding (P = 0.1825);Gain of MoRF binding (P = 0.1825);Gain of MoRF binding (P = 0.1825);Gain of MoRF binding (P = 0.1825);
MVP		1.0
MPC		0.54
ClinPred		0.52	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.85

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: rs398122370; hg19: chr20-4680497;