1-20633622-CCGGCCGGGCCTACGGCTTGGGG-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate

The NM_032409.3(PINK1):c.85_106delTACGGCTTGGGGCGGCCGGGCC(p.Tyr29ArgfsTer71) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,406 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PINK1
NM_032409.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.05

Publications

0 publications found

Variant links:

Genes affected

PINK1 (HGNC:14581): (PTEN induced kinase 1) This gene encodes a serine/threonine protein kinase that localizes to mitochondria. It is thought to protect cells from stress-induced mitochondrial dysfunction. Mutations in this gene cause one form of autosomal recessive early-onset Parkinson disease. [provided by RefSeq, Jul 2008]

PINK1 links:

MIR6084 (HGNC:50235): (microRNA 6084) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6084 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 39 pathogenic variants in the truncated region.

PP5

Variant 1-20633622-CCGGCCGGGCCTACGGCTTGGGG-C is Pathogenic according to our data. Variant chr1-20633622-CCGGCCGGGCCTACGGCTTGGGG-C is described in ClinVar as [Pathogenic]. Clinvar id is 1454290.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PINK1	NM_032409.3 link	c.85_106delTACGGCTTGGGGCGGCCGGGCC	p.Tyr29ArgfsTer71	frameshift_variant	Exon 1 of 8	ENST00000321556.5	NP_115785.1	Q9BXM7-1
MIR6084	NR_106732.1 link	n.-56_-35delCGGCCGGGCCTACGGCTTGGGG		upstream_gene_variant
MIR6084	unassigned_transcript_48	n.-133_-112delCGGCCGGGCCTACGGCTTGGGG		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PINK1	ENST00000321556.5 link	c.85_106delTACGGCTTGGGGCGGCCGGGCC	p.Tyr29ArgfsTer71	frameshift_variant	Exon 1 of 8	1	NM_032409.3	ENSP00000364204.3		Q9BXM7-1
MIR6084	ENST00000622012.1 link	n.-56_-35delCGGCCGGGCCTACGGCTTGGGG		upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151406

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000175

AC:

AN:

1142222

Hom.:

AF XY:

0.00000182

AC XY:

AN XY:

548186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22562

American (AMR)

AF:

0.00

AC:

AN:

8090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14852

East Asian (EAS)

AF:

0.00

AC:

AN:

25432

South Asian (SAS)

AF:

0.00

AC:

AN:

36046

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3118

European-Non Finnish (NFE)

AF:

0.00000104

AC:

AN:

960206

Other (OTH)

AF:

0.0000216

AC:

AN:

46344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151406

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73968

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41338

American (AMR)

AF:

0.00

AC:

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67822

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive early-onset Parkinson disease 6

Pathogenic:1

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Tyr29Argfs*71) in the PINK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PINK1 are known to be pathogenic (PMID: 15087508, 15349870). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1454290). This variant is also known as c.85_106 22bpdel (p.Y29Rfs*70). This premature translational stop signal has been observed in individual(s) with clinical features of Parkinson disease (PMID: 32713623). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=25/175

disease causing (fs/PTC)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over