1-20633744-C-A

Variant names:

• chr1-20633744-C-A
• rs553247784
• NM_032409.3:c.196C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032409.3(PINK1):​c.196C>A​(p.Arg66Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,389,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R66C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PINK1 NM_032409.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46
• Publications: 0 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]

MIR6084 (HGNC:50235): (microRNA 6084) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PINK1	NM_032409.3	c.196C>A	p.Arg66Ser	missense_variant	Exon 1 of 8	ENST00000321556.5	NP_115785.1
MIR6084	NR_106732.1	n.66C>A		non_coding_transcript_exon_variant	Exon 1 of 1
MIR6084	unassigned_transcript_48	n.-12C>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PINK1	ENST00000321556.5	c.196C>A	p.Arg66Ser	missense_variant	Exon 1 of 8	1	NM_032409.3	ENSP00000364204.3
MIR6084	ENST00000622012.1	n.66C>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1389386 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 686434

African (AFR) AF: 0.00 AC: 0 AN: 31850

American (AMR) AF: 0.00 AC: 0 AN: 36122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 36220

South Asian (SAS) AF: 0.00 AC: 0 AN: 79608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5002

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1081564

Other (OTH) AF: 0.00 AC: 0 AN: 57954

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.0047
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.5
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.053	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.32		Loss of MoRF binding (P = 0.0573);
MVP		0.90
MPC		0.75
ClinPred		0.96	D
GERP RS		3.4
PromoterAI		0.0026	Neutral
Varity_R		0.40
gMVP		0.63
Mutation Taster		=69/31	polymorphism

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: rs553247784; hg19: chr1-20960237;