6-161785805-C-T

Variant names:

• chr6-161785805-C-T
• rs72480422
• NM_004562.3:c.838G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004562.3(PRKN):​c.838G>A​(p.Asp280Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,613,910 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.33

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15441981).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKN	NM_004562.3	c.838G>A	p.Asp280Asn	missense_variant	Exon 7 of 12	ENST00000366898.6	NP_004553.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKN	ENST00000366898.6	c.838G>A	p.Asp280Asn	missense_variant	Exon 7 of 12	1	NM_004562.3	ENSP00000355865.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251122 Hom.: 1 AF XY: 0.000184 AC XY: 25 AN XY: 135724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000163 AC: 238 AN: 1461754 Hom.: 1 Cov.: 32 AF XY: 0.000205 AC XY: 149 AN XY: 727172

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000791

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74318

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000664 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive juvenile Parkinson disease 2 Uncertain:1

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.838G>A p.Asp280Asn in the PRKN gene has been reported previously in individuals affected with Parkinson's Disease Bardien et al., 2009; Wang et al., 2008. The variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance.The amino acid Aspartic acid at position 280 is changed to a Asparagine changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence Polyphen - Damaging, SIFT - Tolerated and MutationTaster - Polymorphism predicts conflicting evidence on protein structure and function for this variant. The reference residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

not provided Uncertain:1

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;.;.;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.94	D;D;D;.;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Uncertain	0.14	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.083	T;T;T;T;T;T
Sift4G	Benign	0.089	T;T;T;T;T;T
Polyphen		0.98	D;.;.;.;.;.
Vest4		0.62
MVP		0.95
MPC		0.36
ClinPred		0.19	T
GERP RS		5.8
Varity_R		0.33
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs72480422; hg19: chr6-162206837; COSMIC: COSV100630537;