Variant chr1-20633744-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032409.3(PINK1):c.196C>T(p.Arg66Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000714 in 1,541,588 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PINK1
NM_032409.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PINK1	NM_032409.3 linkuse as main transcript	c.196C>T	p.Arg66Cys	missense_variant	1/8	ENST00000321556.5
MIR6084	NR_106732.1 linkuse as main transcript	n.66C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PINK1	ENST00000321556.5 linkuse as main transcript	c.196C>T	p.Arg66Cys	missense_variant	1/8	1	NM_032409.3	P1	Q9BXM7-1
MIR6084	ENST00000622012.1 linkuse as main transcript	n.66C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00000144

AC:

AN:

1389386

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

686434

show subpopulations

Gnomad4 AFR exome

AF:

0.0000314

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.00000963

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.196C>T (p.R66C) alteration is located in exon 1 (coding exon 1) of the PINK1 gene. This alteration results from a C to T substitution at nucleotide position 196, causing the arginine (R) at amino acid position 66 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.025

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.76

MetaSVM

Uncertain

0.18

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.96

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.48

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.48

MutPred

0.41

Loss of MoRF binding (P = 0.0256);

MVP

0.95

MPC

0.83

ClinPred

0.96

GERP RS

3.4

Varity_R

0.38

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over