chr1-20644526-C-A

Variant names:

• chr1-20644526-C-A
• rs28940284
• NM_032409.3:c.813C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000321556.5(PINK1):​c.813C>A​(p.His271Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. H271H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PINK1 ENST00000321556.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.57
• Publications: 26 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 1-20644526-C-A is Pathogenic according to our data. Variant chr1-20644526-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2405.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000321556.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	NM_032409.3	MANE Select	c.813C>A	p.His271Gln	missense	Exon 4 of 8	NP_115785.1
	PINK1-AS	NR_046507.1		n.3981+1059G>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	ENST00000321556.5	TSL:1 MANE Select	c.813C>A	p.His271Gln	missense	Exon 4 of 8	ENSP00000364204.3
	PINK1	ENST00000492302.1	TSL:2	n.1901C>A		non_coding_transcript_exon	Exon 2 of 5
	PINK1-AS	ENST00000451424.1	TSL:2	n.3981+1059G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive early-onset Parkinson disease 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		1.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.94		Gain of MoRF binding (P = 0.1028)
MVP		0.94
MPC		0.70
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.89
gMVP		0.92
Mutation Taster		=14/86	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: rs28940284; hg19: chr1-20971019;