NM_198578.4:c.4883G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_198578.4(LRRK2):c.4883G>C(p.Arg1628Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000967 in 1,611,674 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1628H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00092 ( 3 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2B:6O:1

Conservation

PhyloP100: 9.23

Publications

266 publications found

Variant links:

Genes affected

LRRK2 (HGNC:18618): (leucine rich repeat kinase 2) This gene is a member of the leucine-rich repeat kinase family and encodes a protein with an ankryin repeat region, a leucine-rich repeat (LRR) domain, a kinase domain, a DFG-like motif, a RAS domain, a GTPase domain, a MLK-like domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Mutations in this gene have been associated with Parkinson disease-8. [provided by RefSeq, Jul 2008]

LRRK2 Gene-Disease associations (from GenCC):

autosomal dominant Parkinson disease 8
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
Parkinson disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hereditary late onset Parkinson disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LRRK2 links:

ENSG00000258167 (HGNC:):

ENSG00000258167 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010469884).

BP6

Variant 12-40320043-G-C is Benign according to our data. Variant chr12-40320043-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 39198.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00141 (214/152114) while in subpopulation EAS AF = 0.0244 (126/5174). AF 95% confidence interval is 0.0209. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 214 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198578.4. 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
	LRRK2	NM_198578.4	MANE Select	c.4883G>C	p.Arg1628Pro	missense	Exon 34 of 51	NP_940980.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.4883G>C	p.Arg1628Pro	missense	Exon 34 of 51	ENSP00000298910.7	Q5S007
LRRK2	ENST00000430804.5	TSL:1	n.*1556G>C		non_coding_transcript_exon	Exon 13 of 30	ENSP00000410821.1	H7C3B6
LRRK2	ENST00000430804.5	TSL:1	n.*1556G>C		3_prime_UTR	Exon 13 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0243

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000574

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00187

AC:

469

AN:

250278

AF XY:

0.00182

show subpopulations

Gnomad AFR exome

AF:

0.000876

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0201

Gnomad FIN exome

AF:

0.000694

Gnomad NFE exome

AF:

0.000512

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000922

AC:

1345

AN:

1459560

Hom.:

Cov.:

AF XY:

0.000921

AC XY:

669

AN XY:

726076

show subpopulations

African (AFR)

AF:

0.000720

AC:

AN:

33354

American (AMR)

AF:

0.0000224

AC:

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00838

AC:

332

AN:

39630

South Asian (SAS)

AF:

0.000361

AC:

AN:

85884

European-Finnish (FIN)

AF:

0.000824

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000758

AC:

842

AN:

1110580

Other (OTH)

AF:

0.00118

AC:

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

128

191

255

319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00141

AC:

214

AN:

152114

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.000939

AC:

AN:

41526

American (AMR)

AF:

0.000197

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.0244

AC:

126

AN:

5174

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000574

AC:

AN:

67956

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000335

Hom.:

Bravo

AF:

0.00126

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00175

AC:

212

Asia WGS

AF:

0.00578

AC:

AN:

3476

EpiCase

AF:

0.000328

EpiControl

AF:

0.000534

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant Parkinson disease 8 (7)

not provided (2)

Autosomal dominant Parkinson disease 8;C1861689:Klippel-Feil syndrome 1, autosomal dominant (1)

Early onset Alzheimer disease with behavioral disturbance (1)

Parkinson disease (1)

Spinocerebellar atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.0032

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.4

PhyloP100

9.2

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.55

Sift

Benign

0.040

Sift4G

Uncertain

0.029

Polyphen

1.0

Vest4

0.90

MVP

0.95

MPC

0.52

ClinPred

0.065

GERP RS

5.5

Varity_R

0.90

gMVP

0.67

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over