6-162727665-T-A

Variant names:

• chr6-162727665-T-A
• rs747682986
• NM_004562.3:c.4A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004562.3(PRKN):​c.4A>T​(p.Ile2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,431,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. I2V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• Publications: 0 publications found

Genes affected

PRKN (HGNC:8607): (parkin RBR E3 ubiquitin protein ligase) The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]

PACRG (HGNC:19152): (parkin coregulated) This gene encodes a protein that is conserved across metazoans. In vertebrates, this gene is linked in a head-to-head arrangement with the adjacent parkin gene, which is associated with autosomal recessive juvenile Parkinson's disease. These genes are co-regulated in various tissues and they share a bi-directional promoter. Both genes are associated with susceptibility to leprosy. The parkin co-regulated gene protein forms a large molecular complex with chaperones, including heat shock proteins 70 and 90, and chaperonin components. This protein is also a component of Lewy bodies in Parkinson's disease patients, and it suppresses unfolded Pael receptor-induced neuronal cell death. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36777934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKN	NM_004562.3	c.4A>T	p.Ile2Leu	missense_variant	Exon 1 of 12	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6	c.4A>T	p.Ile2Leu	missense_variant	Exon 1 of 12	1	NM_004562.3	ENSP00000355865.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1431688 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 709702

African (AFR) AF: 0.00 AC: 0 AN: 32682

American (AMR) AF: 0.00 AC: 0 AN: 40836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25554

East Asian (EAS) AF: 0.00 AC: 0 AN: 37644

South Asian (SAS) AF: 0.00 AC: 0 AN: 82084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1098022

Other (OTH) AF: 0.00 AC: 0 AN: 59144

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.089	T;.;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.61	T;T;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-0.49	T
PhyloP100		1.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.33	N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.68	T;T;D;T
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.43
MutPred		0.38		Loss of catalytic residue at I2 (P = 0.066);Loss of catalytic residue at I2 (P = 0.066);Loss of catalytic residue at I2 (P = 0.066);Loss of catalytic residue at I2 (P = 0.066);
MVP		0.91
MPC		0.055
ClinPred		0.18	T
GERP RS		4.0
PromoterAI		0.026	Neutral
Varity_R		0.20
gMVP		0.21
Mutation Taster		=236/64	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs747682986; hg19: chr6-163148697;