1-20645640-T-C

Variant names:

• chr1-20645640-T-C
• rs28940285
• NM_032409.3:c.1040T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PP3_Strong PP5_Very_Strong

The NM_032409.3(PINK1):​c.1040T>C​(p.Leu347Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000934807: Experimental studies have shown that this missense change affects PINK1 function (PMID:15824318, 17579517, 18359516, 23303188).; SCV002556504: Multiple functional studies have demonstrated that this variant destabilizes PINK1, reduces its kinase activity and affects its function (PMID:15824318; PMID:18359116) (PS3).; SCV006584037: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:15824318, 17579517, 18359116)."; SCV004229841: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID:15824318, 17579517, 19242547, 19880420, 20798600, 23303188); SCV007098373: Published functional studies demonstrate a damaging effect and show that this variant destabilizes the protein and drastically reduces kinase activity (PMID:15824318); Published functional studies in Drosophilia demonstrate a damaging effect and show that this variant fails to translocate Parkin to the mitochondria and induce mitochondrial aggregation (PMID:23303188);".

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PINK1 NM_032409.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 6.97
• Publications: 83 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000934807: Experimental studies have shown that this missense change affects PINK1 function (PMID: 15824318, 17579517, 18359516, 23303188).; SCV002556504: Multiple functional studies have demonstrated that this variant destabilizes PINK1, reduces its kinase activity and affects its function (PMID: 15824318; PMID: 18359116) (PS3).; SCV006584037: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15824318, 17579517, 18359116)."; SCV004229841: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15824318, 17579517, 19242547, 19880420, 20798600, 23303188); SCV007098373: Published functional studies demonstrate a damaging effect and show that this variant destabilizes the protein and drastically reduces kinase activity (PMID: 15824318); Published functional studies in Drosophilia demonstrate a damaging effect and show that this variant fails to translocate Parkin to the mitochondria and induce mitochondrial aggregation (PMID: 23303188)
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 1-20645640-T-C is Pathogenic according to our data. Variant chr1-20645640-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032409.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	NM_032409.3	MANE Select	c.1040T>C	p.Leu347Pro	missense	Exon 5 of 8	NP_115785.1	Q9BXM7-1
	PINK1-AS	NR_046507.1		n.3926A>G		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	ENST00000321556.5	TSL:1 MANE Select	c.1040T>C	p.Leu347Pro	missense	Exon 5 of 8	ENSP00000364204.3	Q9BXM7-1
	PINK1	ENST00000878749.1		c.1040T>C	p.Leu347Pro	missense	Exon 5 of 8	ENSP00000548808.1
	PINK1	ENST00000878743.1		c.1040T>C	p.Leu347Pro	missense	Exon 5 of 8	ENSP00000548802.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251436 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461890 Hom.: 0 Cov.: 37 AF XY: 0.0000124 AC XY: 9 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.000199 AC: 12 AN: 60396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.000131 AC: 2 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000462 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Autosomal recessive early-onset Parkinson disease 6 (7)
4	-	-	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Loss of stability (P = 0.0399)
MVP		0.99
MPC		0.91
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.94
gMVP		0.97
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28940285; hg19: chr1-20972133;