rs2078073

Positions:

• chr1-20651363-T-C

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.*672T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 154,648 control chromosomes in the GnomAD database, including 6,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6024 hom., cov: 34)
  • Exomes 𝑓: 0.29 (124 hom.)
• Consequence: PINK1 NM_032409.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.463

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=-0.84).
• BP6: Variant 1-20651363-T-C is Benign according to our data. Variant chr1-20651363-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 295030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PINK1	NM_032409.3	c.*672T>C		3_prime_UTR_variant	8/8	ENST00000321556.5
PINK1-AS	NR_046507.1	n.831A>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PINK1	ENST00000321556.5	c.*672T>C		3_prime_UTR_variant	8/8	1	NM_032409.3	P1
PINK1-AS	ENST00000451424.1	n.831A>G		non_coding_transcript_exon_variant	1/3	2
PINK1	ENST00000400490.2	n.1511T>C		non_coding_transcript_exon_variant	4/4	2
PINK1	ENST00000492302.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42219 AN: 151986 Hom.: 6021 Cov.: 34

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.287 AC: 729 AN: 2544 Hom.: 124 Cov.: 0 AF XY: 0.296 AC XY: 372 AN XY: 1256

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.266

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.333

Gnomad4 SAS exome AF: 0.419

Gnomad4 FIN exome AF: 0.667

Gnomad4 NFE exome AF: 0.278

Gnomad4 OTH exome AF: 0.289

GnomAD4 genome AF: 0.278 AC: 42239 AN: 152104 Hom.: 6024 Cov.: 34 AF XY: 0.281 AC XY: 20910 AN XY: 74364

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.359

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.353

Gnomad4 NFE AF: 0.276

Gnomad4 OTH AF: 0.266

Alfa AF: 0.275 Hom.: 2263

Bravo AF: 0.269

Asia WGS AF: 0.327 AC: 1134 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital disorder of glycosylation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2021

- -

Parkinson Disease, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal recessive early-onset Parkinson disease 6 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.91
DANN	Benign	0.66

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

Other links and lift over

dbSNP: rs2078073; hg19: chr1-20977856;