chr12-40340400-G-A

Variant names:

• chr12-40340400-G-A
• rs34637584
• NM_198578.4:c.6055G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 13P and 5B. PS3 PP3 PP5_Very_Strong BP4 BS2

The NM_198578.4(LRRK2):​c.6055G>A​(p.Gly2019Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,613,804 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 Likely pathogenic,risk factor (★★). ClinVar reports functional evidence for this variant: "SCV000640135: Experimental studies have shown that this missense change affects LRRK2 function (PMID:26251043)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic; risk factor criteria provided, multiple submitters, no conflicts P:28 O:2
• Conservation: PhyloP100: 9.66
• Publications: 3324 publications found

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

ENSG00000258167 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000640135: Experimental studies have shown that this missense change affects LRRK2 function (PMID: 26251043).; SCV002034786: Functional studies showed increased mitochondrial DNA damage in iPSC-derived neural cells from patients carrying the p.Gly2019Ser variant than in cells from healthy controls. In patient cells in which the p.Gly2019Ser variant was repaired with zinc finger nuclease, reduced mitochondrial DNA damage was observed at levels seen in healthy control cells (Sanders et al. 2014). The p.Gly2019Ser variant has also been demonstrated to result in enlarged lysosomes, impaired lysosomal function, and increased kinase activity (Henry et al. 2015).; SCV002050743: At least one publication reports experimental evidence evaluating an impact on protein function (example, Greggio_2006). The most pronounced variant effect results in increased tendency to form inclusion bodies. Secondly, neurons and neuronal cell lines undergo cell death after expression of mutant protein.; SCV005045124: Functional studies show increased mitochondrial DNA damage, increased phosphorylation of alpha synuclein, dysregulation of lysosomal function, and kinase-dependent neurodegeneration (Henry G et al., PMID: 26251043; Qing H et al., PMID: 19576176; Sanders LH et al., PMID: 24148854; Vermilyea SC et al., PMID: 29402177), indicating that this variant impacts protein function.; SCV007097224: Pathogenic missense variants have been shown to increase kinase activity, and consequently result in neurotoxicity (PMID: 17200152);; SCV000329408: published functional studies have shown that expression of G2019S produces enlarged lysosomes and alters their function (Henry et al., 2015); SCV000842686: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 29402177, 29386392, 26251043, 23472874, 27413152, 35732218); SCV001250090: PS3:Supporting; SCV000742130: Functional analysis demonstrated that compared to the wild-type, the p.G2019S alteration significantly increased the phosphorylation of peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin peroxidases. Increased PRDX3 phosphorylation was associated with inhibited PRDX3 peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells (Angeles, 2011).; SCV004112443: Functional studies showed that this variant activated kinase activity, enlarged lysosomes and diminished the lysosomal capacity (Jaleel et al. 2007. PubMed ID: 17447891; West et al. 2007. PubMed ID: 17200152; Henry et al. 2015. PubMed ID: 26251043).; SCV004812567: A transgenic mouse model for the variant recapitulates the human PD phenotype and brain histopathology (PMID: 22539006).
• PP3: Multiple lines of computational evidence support a deleterious effect 12: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 12-40340400-G-A is Pathogenic according to our data. Variant chr12-40340400-G-A is described in ClinVar as Pathogenic/Likely_pathogenic|risk_factor. ClinVar VariationId is 1940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15880463). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 55 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.6055G>A	p.Gly2019Ser	missense	Exon 41 of 51	NP_940980.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.6055G>A	p.Gly2019Ser	missense	Exon 41 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000430804.5	TSL:1	n.*2728G>A		non_coding_transcript_exon	Exon 20 of 30	ENSP00000410821.1	H7C3B6
	LRRK2	ENST00000430804.5	TSL:1	n.*2728G>A		3_prime_UTR	Exon 20 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152064 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000526 AC: 132 AN: 251154 AF XY: 0.000553

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00854

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000417 AC: 609 AN: 1461622 Hom.: 1 Cov.: 31 AF XY: 0.000413 AC XY: 300 AN XY: 727112

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.000403 AC: 18 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00785 AC: 205 AN: 26126

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.000274 AC: 305 AN: 1111818

Other (OTH) AF: 0.00111 AC: 67 AN: 60386

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74402

African (AFR) AF: 0.0000723 AC: 3 AN: 41504

American (AMR) AF: 0.000851 AC: 13 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68008

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000650 Hom.: 2

Bravo AF: 0.000586

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000387 AC: 47

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic; risk factor

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	-	-	Autosomal dominant Parkinson disease 8 (18)
7	-	-	not provided (7)
1	-	-	Inborn genetic diseases (1)
1	-	-	LRRK2-related disorder (1)
1	-	-	Parkinson disease (1)
1	-	-	Parkinson disease, late-onset (1)
-	-	-	Young-onset Parkinson disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.16	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.98
MPC		1.8
ClinPred		0.18	T
GERP RS		5.7
Varity_R		0.88
gMVP		0.92
Mutation Taster		=35/65	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs34637584; hg19: chr12-40734202; COSMIC: COSV54172342;