rs45530340

Positions:

• chr1-20633737-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032409.3(PINK1):​c.189C>T​(p.Leu63=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,537,436 control chromosomes in the GnomAD database, including 28,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2121 hom., cov: 32)
  • Exomes 𝑓: 0.19 (25996 hom.)
• Consequence: PINK1 NM_032409.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.15

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-20633737-C-T is Benign according to our data. Variant chr1-20633737-C-T is described in ClinVar as [Benign]. Clinvar id is 262026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-20633737-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PINK1	NM_032409.3	c.189C>T	p.Leu63=	synonymous_variant	1/8	ENST00000321556.5	NP_115785.1
MIR6084	NR_106732.1	n.59C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PINK1	ENST00000321556.5	c.189C>T	p.Leu63=	synonymous_variant	1/8	1	NM_032409.3	ENSP00000364204	P1
MIR6084	ENST00000622012.1	n.59C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23658 AN: 151890 Hom.: 2119 Cov.: 32

Gnomad AFR AF: 0.0662

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.176 AC: 23446 AN: 133556 Hom.: 2227 AF XY: 0.178 AC XY: 13042 AN XY: 73426

Gnomad AFR exome AF: 0.0662

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.149

Gnomad SAS exome AF: 0.154

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.190 AC: 263229 AN: 1385438 Hom.: 25996 Cov.: 36 AF XY: 0.190 AC XY: 129910 AN XY: 684130

Gnomad4 AFR exome AF: 0.0650

Gnomad4 AMR exome AF: 0.151

Gnomad4 ASJ exome AF: 0.265

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.153

Gnomad4 FIN exome AF: 0.181

Gnomad4 NFE exome AF: 0.198

Gnomad4 OTH exome AF: 0.186

GnomAD4 genome AF: 0.156 AC: 23651 AN: 151998 Hom.: 2121 Cov.: 32 AF XY: 0.153 AC XY: 11393 AN XY: 74308

Gnomad4 AFR AF: 0.0660

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.267

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.185

Alfa AF: 0.192 Hom.: 704

Bravo AF: 0.151

Asia WGS AF: 0.134 AC: 464 AN: 3458

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 24% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 22. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2017	- -

Autosomal recessive early-onset Parkinson disease 6 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.89

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: rs45530340; hg19: chr1-20960230; COSMIC: COSV58630221; COSMIC: COSV58630221;