rs3738136

Variant names:

• chr1-20645618-G-A
• rs3738136
• NM_032409.3:c.1018G>A

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:9
• Conservation: PhyloP100: 1.03
• Publications: 46 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 295004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PINK1	NM_032409.3	c.1018G>A	p.Ala340Thr	missense_variant	Exon 5 of 8	ENST00000321556.5	NP_115785.1
PINK1-AS	NR_046507.1	n.3948C>T		non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PINK1	ENST00000321556.5	c.1018G>A	p.Ala340Thr	missense_variant	Exon 5 of 8	1	NM_032409.3	ENSP00000364204.3
PINK1	ENST00000400490.2	n.111G>A		non_coding_transcript_exon_variant	Exon 1 of 4	2
PINK1-AS	ENST00000451424.1	n.3948C>T		non_coding_transcript_exon_variant	Exon 2 of 3	2
PINK1	ENST00000492302.1	n.2106G>A		non_coding_transcript_exon_variant	Exon 3 of 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

GnomAD2 exomes AF: 0.0921 AC: 23161 AN: 251368 AF XY: 0.0971

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 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

African (AFR) AF: 0.0130 AC: 434 AN: 33480

American (AMR) AF: 0.0947 AC: 4236 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0413 AC: 1079 AN: 26136

East Asian (EAS) AF: 0.258 AC: 10228 AN: 39694

South Asian (SAS) AF: 0.215 AC: 18563 AN: 86258

European-Finnish (FIN) AF: 0.0929 AC: 4962 AN: 53398

Middle Eastern (MID) AF: 0.0371 AC: 214 AN: 5766

European-Non Finnish (NFE) AF: 0.0460 AC: 51105 AN: 1111972

Other (OTH) AF: 0.0710 AC: 4285 AN: 60388

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

African (AFR) AF: 0.0163 AC: 678 AN: 41472

American (AMR) AF: 0.0629 AC: 959 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 147 AN: 3468

East Asian (EAS) AF: 0.260 AC: 1333 AN: 5126

South Asian (SAS) AF: 0.229 AC: 1097 AN: 4800

European-Finnish (FIN) AF: 0.0869 AC: 916 AN: 10538

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0448 AC: 3047 AN: 67974

Other (OTH) AF: 0.0474 AC: 100 AN: 2108

Alfa AF: 0.0491 Hom.: 1330

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 26% 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: 24. Only high quality variants are reported. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive early-onset Parkinson disease 6 Benign:3

Mar 06, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

PINK1-related disorder Benign:1

Mar 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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
PhyloP100		1.0
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
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3738136; hg19: chr1-20972111; COSMIC: COSV58631402;