1-20633892-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032409.3(PINK1):c.344A>T(p.Gln115Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0459 in 1,582,768 control chromosomes in the GnomAD database, including 1,905 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q115H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.035 ( 139 hom., cov: 31)

Exomes 𝑓: 0.047 ( 1766 hom. )

Consequence

PINK1
NM_032409.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.17

Publications

24 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015456975).

BP6

Variant 1-20633892-A-T is Benign according to our data. Variant chr1-20633892-A-T is described in ClinVar as Benign. ClinVar VariationId is 294999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PINK1	NM_032409.3 link	c.344A>T	p.Gln115Leu	missense_variant	Exon 1 of 8	ENST00000321556.5	NP_115785.1
MIR6084	NR_106732.1 link	n.*104A>T		downstream_gene_variant
MIR6084	unassigned_transcript_48	n.*117A>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PINK1	ENST00000321556.5 link	c.344A>T	p.Gln115Leu	missense_variant	Exon 1 of 8	1	NM_032409.3	ENSP00000364204.3
MIR6084	ENST00000622012.1 link	n.*104A>T		downstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.0354

AC:

5352

AN:

151192

Hom.:

139

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00966

Gnomad AMI

AF:

0.0954

Gnomad AMR

AF:

0.0301

Gnomad ASJ

AF:

0.0349

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.00583

Gnomad FIN

AF:

0.0447

Gnomad MID

AF:

0.0256

Gnomad NFE

AF:

0.0548

Gnomad OTH

AF:

0.0304

GnomAD2 exomes

AF:

0.0333

AC:

6238

AN:

187552

AF XY:

0.0333

show subpopulations

Gnomad AFR exome

AF:

0.00788

Gnomad AMR exome

AF:

0.0204

Gnomad ASJ exome

AF:

0.0354

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0411

Gnomad NFE exome

AF:

0.0541

Gnomad OTH exome

AF:

0.0390

GnomAD4 exome

AF:

0.0470

AC:

67226

AN:

1431472

Hom.:

1766

Cov.:

AF XY:

0.0457

AC XY:

32427

AN XY:

709674

show subpopulations

African (AFR)

AF:

0.00730

AC:

240

AN:

32898

American (AMR)

AF:

0.0218

AC:

887

AN:

40716

Ashkenazi Jewish (ASJ)

AF:

0.0348

AC:

891

AN:

25584

East Asian (EAS)

AF:

0.0000523

AC:

AN:

38218

South Asian (SAS)

AF:

0.00704

AC:

579

AN:

82258

European-Finnish (FIN)

AF:

0.0446

AC:

2163

AN:

48516

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5322

European-Non Finnish (NFE)

AF:

0.0548

AC:

60192

AN:

1098794

Other (OTH)

AF:

0.0374

AC:

2214

AN:

59166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

4120

8240

12361

16481

20601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2170

4340

6510

8680

10850

<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

AF:

0.0354

AC:

5349

AN:

151296

Hom.:

139

Cov.:

AF XY:

0.0339

AC XY:

2507

AN XY:

73926

show subpopulations

African (AFR)

AF:

0.00964

AC:

396

AN:

41094

American (AMR)

AF:

0.0300

AC:

456

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.0349

AC:

121

AN:

3464

East Asian (EAS)

AF:

0.000197

AC:

AN:

5072

South Asian (SAS)

AF:

0.00584

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.0447

AC:

467

AN:

10450

Middle Eastern (MID)

AF:

0.0274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0548

AC:

3722

AN:

67904

Other (OTH)

AF:

0.0301

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

263

527

790

1054

1317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0475

Hom.:

Bravo

AF:

0.0326

TwinsUK

AF:

0.0380

AC:

141

ALSPAC

AF:

0.0449

AC:

173

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.0450

AC:

360

ExAC

AF:

0.0284

AC:

3311

Asia WGS

AF:

0.00433

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive early-onset Parkinson disease 6

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 14, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.055

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.3

PhyloP100

1.2

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.10

REVEL

Benign

0.11

Sift

Benign

0.32

Sift4G

Benign

0.20

Polyphen

0.12

Vest4

0.098

MPC

0.17

ClinPred

0.0044

GERP RS

3.9

PromoterAI

-0.0025

Neutral

(source)

Varity_R

0.11

gMVP

0.49

Mutation Taster

=84/16

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over