Genetic Variant NM_032409.3:c.189C>A (chr1-20633737-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_032409.3(PINK1):c.189C>A(p.Leu63Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000361 in 1,385,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L63L) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

PINK1
NM_032409.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.15

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP7

Synonymous conserved (PhyloP=-1.14 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	NM_032409.3	MANE Select	c.189C>A	p.Leu63Leu	synonymous	Exon 1 of 8	NP_115785.1
	MIR6084	NR_106732.1		n.59C>A		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	ENST00000321556.5	TSL:1 MANE Select	c.189C>A	p.Leu63Leu	synonymous	Exon 1 of 8	ENSP00000364204.3
	MIR6084	ENST00000622012.1	TSL:6	n.59C>A		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000361

AC:

AN:

1385480

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

684150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31638

American (AMR)

AF:

0.00

AC:

AN:

35812

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25116

East Asian (EAS)

AF:

0.00

AC:

AN:

35978

South Asian (SAS)

AF:

0.00

AC:

AN:

79360

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4792

European-Non Finnish (NFE)

AF:

0.00000463

AC:

AN:

1079676

Other (OTH)

AF:

0.00

AC:

AN:

57836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.67

PhyloP100

-1.1

PromoterAI

-0.051

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over