rs3738136

chr1-20645618-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032409.3(PINK1):c.1018G>A(p.Ala340Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0641 in 1,613,752 control chromosomes in the GnomAD database, including 5,875 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (462 hom., cov: 31)
  • Exomes 𝑓: 0.065 (5413 hom.)
• Consequence: PINK1 NM_032409.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.03

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-AS (HGNC:38872): (PINK1 antisense RNA)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056702495).
• BP6: Variant 1-20645618-G-A is Benign according to our data. Variant chr1-20645618-G-A is described in ClinVar as [Benign]. Clinvar id is 295004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-20645618-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PINK1	NM_032409.3	c.1018G>A	p.Ala340Thr	missense_variant	5/8	ENST00000321556.5
PINK1-AS	NR_046507.1	n.3948C>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PINK1	ENST00000321556.5	c.1018G>A	p.Ala340Thr	missense_variant	5/8	1	NM_032409.3	P1
PINK1-AS	ENST00000451424.1	n.3948C>T		non_coding_transcript_exon_variant	2/3	2
PINK1	ENST00000400490.2	n.111G>A		non_coding_transcript_exon_variant	1/4	2
PINK1	ENST00000492302.1	n.2106G>A		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes AF: 0.0548 AC: 8320 AN: 151828 Hom.: 461 Cov.: 31

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0627

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0479

GnomAD3 exomes AF: 0.0921 AC: 23161 AN: 251368 Hom.: 1876 AF XY: 0.0971 AC XY: 13192 AN XY: 135880

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.0362

Gnomad EAS exome AF: 0.265

Gnomad SAS exome AF: 0.216

Gnomad FIN exome AF: 0.0930

Gnomad NFE exome AF: 0.0451

Gnomad OTH exome AF: 0.0701

GnomAD4 exome AF: 0.0651 AC: 95106 AN: 1461814 Hom.: 5413 Cov.: 38 AF XY: 0.0696 AC XY: 50621 AN XY: 727216

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.0947

Gnomad4 ASJ exome AF: 0.0413

Gnomad4 EAS exome AF: 0.258

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.0929

Gnomad4 NFE exome AF: 0.0460

Gnomad4 OTH exome AF: 0.0710

GnomAD4 genome AF: 0.0547 AC: 8316 AN: 151938 Hom.: 462 Cov.: 31 AF XY: 0.0600 AC XY: 4459 AN XY: 74268

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.0629

Gnomad4 ASJ AF: 0.0424

Gnomad4 EAS AF: 0.260

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.0869

Gnomad4 NFE AF: 0.0448

Gnomad4 OTH AF: 0.0474

Alfa AF: 0.0484 Hom.: 689

Bravo AF: 0.0496

TwinsUK AF: 0.0440 AC: 163

ALSPAC AF: 0.0446 AC: 172

ESP6500AA AF: 0.0182 AC: 80

ESP6500EA AF: 0.0473 AC: 407

ExAC AF: 0.0921 AC: 11176

Asia WGS AF: 0.203 AC: 703 AN: 3478

EpiCase AF: 0.0425

EpiControl AF: 0.0451

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive early-onset Parkinson disease 6 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Invitae	Jan 30, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2018

This variant is associated with the following publications: (PMID: 23459931, 17084972, 31182772) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	9.7
Dann	Benign	0.76
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.42	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.054
MPC		0.17
ClinPred		0.0016	T
GERP RS		2.4
Varity_R		0.015
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3738136; hg19: chr1-20972111; COSMIC: COSV58631402;