NM_032409.3:c.13C>T

Variant names:

• chr1-20633561-C-T
• rs1005937012
• NM_032409.3:c.13C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_032409.3(PINK1):​c.13C>T​(p.Gln5*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000846 in 1,182,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000078 (0 hom.)
• Consequence: PINK1 NM_032409.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.75
• Publications: 0 publications found

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]

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]

ACMG classification

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 41 pathogenic variants in the truncated region.
• PP5: Variant 1-20633561-C-T is Pathogenic according to our data. Variant chr1-20633561-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 661098.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032409.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	NM_032409.3	MANE Select	c.13C>T	p.Gln5*	stop_gained	Exon 1 of 8	NP_115785.1	Q9BXM7-1
	MIR6084	NR_106732.1		n.-118C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	ENST00000321556.5	TSL:1 MANE Select	c.13C>T	p.Gln5*	stop_gained	Exon 1 of 8	ENSP00000364204.3	Q9BXM7-1
	PINK1	ENST00000878749.1		c.13C>T	p.Gln5*	stop_gained	Exon 1 of 8	ENSP00000548808.1
	PINK1	ENST00000878743.1		c.13C>T	p.Gln5*	stop_gained	Exon 1 of 8	ENSP00000548802.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000776 AC: 8 AN: 1031464 Hom.: 0 Cov.: 30 AF XY: 0.00000206 AC XY: 1 AN XY: 486252

African (AFR) AF: 0.00 AC: 0 AN: 20992

American (AMR) AF: 0.00 AC: 0 AN: 6788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12032

East Asian (EAS) AF: 0.00 AC: 0 AN: 21732

South Asian (SAS) AF: 0.00 AC: 0 AN: 19118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2658

European-Non Finnish (NFE) AF: 0.00000900 AC: 8 AN: 888784

Other (OTH) AF: 0.00 AC: 0 AN: 39922

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151202 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73826

African (AFR) AF: 0.00 AC: 0 AN: 41328

American (AMR) AF: 0.000132 AC: 2 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67712

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive early-onset Parkinson disease 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.72	D
PhyloP100		2.7
Vest4		0.55
GERP RS		3.7
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=12/188	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1005937012; hg19: chr1-20960054;