rs1043502

Positions:

• chr1-20651255-T-G

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.*564T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 165,700 control chromosomes in the GnomAD database, including 6,601 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 (6000 hom., cov: 35)
  • Exomes 𝑓: 0.27 (601 hom.)
• Consequence: PINK1 NM_032409.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.229

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=-0.81).
• BP6: Variant 1-20651255-T-G is Benign according to our data. Variant chr1-20651255-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 295024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PINK1	NM_032409.3	c.*564T>G		3_prime_UTR_variant	8/8	ENST00000321556.5
PINK1-AS	NR_046507.1	n.939A>C		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PINK1	ENST00000321556.5	c.*564T>G		3_prime_UTR_variant	8/8	1	NM_032409.3	P1
PINK1-AS	ENST00000451424.1	n.939A>C		non_coding_transcript_exon_variant	1/3	2
PINK1	ENST00000400490.2	n.1403T>G		non_coding_transcript_exon_variant	4/4	2
PINK1	ENST00000492302.1	n.3760T>G		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42098 AN: 151728 Hom.: 5997 Cov.: 35

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.266 AC: 3692 AN: 13870 Hom.: 601 Cov.: 0 AF XY: 0.273 AC XY: 1930 AN XY: 7072

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.229

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.323

Gnomad4 SAS exome AF: 0.350

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.257

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.277 AC: 42118 AN: 151830 Hom.: 6000 Cov.: 35 AF XY: 0.281 AC XY: 20854 AN XY: 74198

Gnomad4 AFR AF: 0.263

Gnomad4 AMR AF: 0.235

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.349

Gnomad4 SAS AF: 0.384

Gnomad4 FIN AF: 0.352

Gnomad4 NFE AF: 0.275

Gnomad4 OTH AF: 0.267

Alfa AF: 0.273 Hom.: 2244

Bravo AF: 0.268

Asia WGS AF: 0.314 AC: 1091 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital disorder of glycosylation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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 12, 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	-0.81
CADD	Benign	1.6
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1043502; hg19: chr1-20977748;