rs45499398

chr1-20648554-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032409.3(PINK1):c.1173T>C(p.Asp391=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,614,130 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (18 hom.)
• Consequence: PINK1 NM_032409.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.394

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-20648554-T-C is Benign according to our data. Variant chr1-20648554-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 534248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.394 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1655/152280) while in subpopulation AFR AF= 0.0372 (1544/41548). AF 95% confidence interval is 0.0356. There are 28 homozygotes in gnomad4. There are 752 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PINK1	NM_032409.3	c.1173T>C	p.Asp391=	synonymous_variant	6/8	ENST00000321556.5
PINK1-AS	NR_046507.1	n.3640A>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PINK1	ENST00000321556.5	c.1173T>C	p.Asp391=	synonymous_variant	6/8	1	NM_032409.3	P1
PINK1-AS	ENST00000451424.1	n.3640A>G		non_coding_transcript_exon_variant	1/3	2
PINK1	ENST00000400490.2	n.266T>C		non_coding_transcript_exon_variant	2/4	2
PINK1	ENST00000492302.1	n.2261T>C		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1653 AN: 152162 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00302 AC: 758 AN: 251254 Hom.: 14 AF XY: 0.00219 AC XY: 298 AN XY: 135856

Gnomad AFR exome AF: 0.0392

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00106 AC: 1546 AN: 1461850 Hom.: 18 Cov.: 31 AF XY: 0.000897 AC XY: 652 AN XY: 727224

Gnomad4 AFR exome AF: 0.0349

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.0109 AC: 1655 AN: 152280 Hom.: 28 Cov.: 33 AF XY: 0.0101 AC XY: 752 AN XY: 74468

Gnomad4 AFR AF: 0.0372

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00581 Hom.: 12

Bravo AF: 0.0124

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

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	Invitae	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 18, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	5.0
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs45499398; hg19: chr1-20975047;