rs33958906

chr12-40314059-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 5.49

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 39193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40314059-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 4497 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.4624C>T	p.Pro1542Ser	missense_variant	32/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.4624C>T	p.Pro1542Ser	missense_variant	32/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4497 AN: 151836 Hom.: 145 Cov.: 32

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

GnomAD3 exomes AF: 0.0318 AC: 7966 AN: 250762 Hom.: 277 AF XY: 0.0318 AC XY: 4309 AN XY: 135522

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 SAS exome AF: 0.00928

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.: 31 AF XY: 0.0314 AC XY: 22843 AN XY: 726462

Gnomad4 AFR exome AF: 0.00356

Gnomad4 AMR exome AF: 0.0226

Gnomad4 ASJ exome AF: 0.0178

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00942

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.0322

Gnomad4 OTH exome AF: 0.0294

GnomAD4 genome AF: 0.0296 AC: 4497 AN: 151954 Hom.: 145 Cov.: 32 AF XY: 0.0329 AC XY: 2447 AN XY: 74266

Gnomad4 AFR AF: 0.00531

Gnomad4 AMR AF: 0.0192

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00727

Gnomad4 FIN AF: 0.138

Gnomad4 NFE AF: 0.0350

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0288 Hom.: 109

Bravo AF: 0.0188

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0275 AC: 106

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0329 AC: 283

ExAC AF: 0.0300 AC: 3645

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0298

EpiControl AF: 0.0264

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 30, 2021	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	This variant is associated with the following publications: (PMID: 32677286, 26503572) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.23
Sift	Benign	0.16	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.98	D
Vest4		0.49
MPC		0.42
ClinPred		0.028	T
GERP RS		5.8
Varity_R		0.11
gMVP		0.78

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: rs33958906; hg19: chr12-40707861;