LRRK2 p.Pro1542Ser

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198578.4(LRRK2):c.4624C>T(p.Pro1542Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0315 in 1,612,210 control chromosomes in the GnomAD database, including 1,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1542P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.030 ( 145 hom., cov: 32)

Exomes 𝑓: 0.032 ( 1065 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 5.49

Publications

33 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

new If you want to explore the variant's impact on the transcript NM_198578.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028391778).

BP6

Variant 12-40314059-C-T is Benign according to our data. Variant chr12-40314059-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 39193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0296 (4497/151954) while in subpopulation NFE AF = 0.035 (2380/67924). AF 95% confidence interval is 0.0339. There are 145 homozygotes in GnomAd4. There are 2447 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4497 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.4624C>T	p.Pro1542Ser	missense	Exon 32 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.4624C>T	p.Pro1542Ser	missense	Exon 32 of 51	ENSP00000298910.7	Q5S007
LRRK2	ENST00000430804.5	TSL:1	n.*1297C>T		non_coding_transcript_exon	Exon 11 of 30	ENSP00000410821.1	H7C3B6
LRRK2	ENST00000430804.5	TSL:1	n.*1297C>T		3_prime_UTR	Exon 11 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes

AF:

0.0296

AC:

4497

AN:

151836

Hom.:

145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00532

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0192

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00726

Gnomad FIN

AF:

0.138

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0350

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0318

AC:

7966

AN:

250762

AF XY:

0.0318

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.0235

Gnomad ASJ exome

AF:

0.0174

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.0324

Gnomad OTH exome

AF:

0.0306

GnomAD4 exome

AF:

0.0317

AC:

46326

AN:

1460256

Hom.:

1065

Cov.:

AF XY:

0.0314

AC XY:

22843

AN XY:

726462

show subpopulations

African (AFR)

AF:

0.00356

AC:

119

AN:

33404

American (AMR)

AF:

0.0226

AC:

1007

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.0178

AC:

464

AN:

26074

East Asian (EAS)

AF:

0.000151

AC:

AN:

39646

South Asian (SAS)

AF:

0.00942

AC:

812

AN:

86222

European-Finnish (FIN)

AF:

0.120

AC:

6377

AN:

53356

Middle Eastern (MID)

AF:

0.00903

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0322

AC:

35719

AN:

1110862

Other (OTH)

AF:

0.0294

AC:

1770

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

2180

4360

6540

8720

10900

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1310

2620

3930

5240

6550

<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:

0.0296

AC:

4497

AN:

151954

Hom.:

145

Cov.:

AF XY:

0.0329

AC XY:

2447

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.00531

AC:

220

AN:

41464

American (AMR)

AF:

0.0192

AC:

292

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3464

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00727

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.138

AC:

1453

AN:

10552

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0350

AC:

2380

AN:

67924

Other (OTH)

AF:

0.0175

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

202

403

605

806

1008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0267

Hom.:

127

Bravo

AF:

0.0188

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0298

EpiControl

AF:

0.0264

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant Parkinson disease 8 (4)

not provided (3)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.6

PhyloP100

5.5

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.7

REVEL

Benign

0.23

Sift

Benign

0.16

Sift4G

Uncertain

0.0060

Varity_R

0.11

gMVP

0.78

Mutation Taster

=79/21

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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