1-20633892-A-T

Position:

chr1-20633892-A-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 294999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-20633892-A-T is described in Lovd as [Likely_benign]. Variant chr1-20633892-A-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
PINK1	NM_032409.3 linkuse as main transcript	c.344A>T	p.Gln115Leu	missense_variant	1/8	ENST00000321556.5	NP_115785.1	Q9BXM7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PINK1	ENST00000321556.5 linkuse as main transcript	c.344A>T	p.Gln115Leu	missense_variant	1/8	1	NM_032409.3	ENSP00000364204.3		Q9BXM7-1

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

GnomAD3 exomes

AF:

0.0333

AC:

6238

AN:

187552

Hom.:

147

AF XY:

0.0333

AC XY:

3444

AN XY:

103506

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 SAS exome

AF:

0.00624

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

Gnomad4 AFR exome

AF:

0.00730

Gnomad4 AMR exome

AF:

0.0218

Gnomad4 ASJ exome

AF:

0.0348

Gnomad4 EAS exome

AF:

0.0000523

Gnomad4 SAS exome

AF:

0.00704

Gnomad4 FIN exome

AF:

0.0446

Gnomad4 NFE exome

AF:

0.0548

Gnomad4 OTH exome

AF:

0.0374

GnomAD4 genome

AF:

0.0354

AC:

5349

AN:

151296

Hom.:

139

Cov.:

AF XY:

0.0339

AC XY:

2507

AN XY:

73926

show subpopulations

Gnomad4 AFR

AF:

0.00964

Gnomad4 AMR

AF:

0.0300

Gnomad4 ASJ

AF:

0.0349

Gnomad4 EAS

AF:

0.000197

Gnomad4 SAS

AF:

0.00584

Gnomad4 FIN

AF:

0.0447

Gnomad4 NFE

AF:

0.0548

Gnomad4 OTH

AF:

0.0301

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive early-onset Parkinson disease 6

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

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

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

Varity_R

0.11

gMVP

0.49

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