1-20645555-G-A

Position:

• chr1-20645555-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.960-5G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.869 in 1,611,824 control chromosomes in the GnomAD database, including 610,277 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (53621 hom., cov: 27)
  • Exomes 𝑓: 0.87 (556656 hom.)
• Consequence: PINK1 NM_032409.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002494
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.90

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 (BayesDel_noAF=-0.74).
• BP6: Variant 1-20645555-G-A is Benign according to our data. Variant chr1-20645555-G-A is described in ClinVar as [Benign]. Clinvar id is 262028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-20645555-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PINK1	NM_032409.3	c.960-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000321556.5
PINK1-AS	NR_046507.1	n.3981+30C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PINK1	ENST00000321556.5	c.960-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_032409.3	P1
PINK1-AS	ENST00000451424.1	n.3981+30C>T		intron_variant, non_coding_transcript_variant		2
PINK1	ENST00000400490.2	n.48G>A		non_coding_transcript_exon_variant	1/4	2
PINK1	ENST00000492302.1	n.2048-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.842 AC: 126742 AN: 150610 Hom.: 53586 Cov.: 27

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.838

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.903

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.883

Gnomad FIN AF: 0.927

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.878

Gnomad OTH AF: 0.863

GnomAD3 exomes AF: 0.862 AC: 216185 AN: 250826 Hom.: 93518 AF XY: 0.867 AC XY: 117629 AN XY: 135624

Gnomad AFR exome AF: 0.767

Gnomad AMR exome AF: 0.809

Gnomad ASJ exome AF: 0.900

Gnomad EAS exome AF: 0.808

Gnomad SAS exome AF: 0.886

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.877

Gnomad OTH exome AF: 0.872

GnomAD4 exome AF: 0.872 AC: 1274286 AN: 1461098 Hom.: 556656 Cov.: 57 AF XY: 0.873 AC XY: 634719 AN XY: 726872

Gnomad4 AFR exome AF: 0.755

Gnomad4 AMR exome AF: 0.807

Gnomad4 ASJ exome AF: 0.900

Gnomad4 EAS exome AF: 0.789

Gnomad4 SAS exome AF: 0.884

Gnomad4 FIN exome AF: 0.927

Gnomad4 NFE exome AF: 0.877

Gnomad4 OTH exome AF: 0.869

GnomAD4 genome AF: 0.841 AC: 126826 AN: 150726 Hom.: 53621 Cov.: 27 AF XY: 0.844 AC XY: 61980 AN XY: 73458

Gnomad4 AFR AF: 0.765

Gnomad4 AMR AF: 0.810

Gnomad4 ASJ AF: 0.903

Gnomad4 EAS AF: 0.794

Gnomad4 SAS AF: 0.884

Gnomad4 FIN AF: 0.927

Gnomad4 NFE AF: 0.878

Gnomad4 OTH AF: 0.864

Alfa AF: 0.872 Hom.: 28261

Bravo AF: 0.830

Asia WGS AF: 0.818 AC: 2843 AN: 3476

EpiCase AF: 0.880

EpiControl AF: 0.883

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 90% 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: 84. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal recessive early-onset Parkinson disease 6 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.29
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.080		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: rs3131713; hg19: chr1-20972048;