rs10878245

Variant names:

• chr12-40237989-T-C
• rs10878245
• NM_198578.4:c.457T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-40237989-T-C
• chr12-40237989-T-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198578.4(LRRK2):​c.457T>C​(p.Leu153Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 1,609,940 control chromosomes in the GnomAD database, including 279,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20577 hom., cov: 32)
  • Exomes 𝑓: 0.59 (258528 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.562
• Publications: 39 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 12-40237989-T-C is Benign according to our data. Variant chr12-40237989-T-C is described in ClinVar as Benign. ClinVar VariationId is 39192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.562 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

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.457T>C	p.Leu153Leu	synonymous	Exon 5 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.457T>C	p.Leu153Leu	synonymous	Exon 5 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000950031.1		c.457T>C	p.Leu153Leu	synonymous	Exon 5 of 51	ENSP00000620090.1
	LRRK2	ENST00000680790.1		c.457T>C	p.Leu153Leu	synonymous	Exon 5 of 49	ENSP00000505335.1	A0A7P0T8S1

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77337 AN: 151896 Hom.: 20563 Cov.: 32

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.357

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.512

GnomAD2 exomes AF: 0.521 AC: 130500 AN: 250672 AF XY: 0.535

Gnomad AFR exome AF: 0.383

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.349

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.531

GnomAD4 exome AF: 0.590 AC: 859695 AN: 1457926 Hom.: 258528 Cov.: 37 AF XY: 0.591 AC XY: 428840 AN XY: 725502

African (AFR) AF: 0.380 AC: 12682 AN: 33402

American (AMR) AF: 0.339 AC: 15137 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 13913 AN: 26090

East Asian (EAS) AF: 0.351 AC: 13884 AN: 39602

South Asian (SAS) AF: 0.610 AC: 52558 AN: 86152

European-Finnish (FIN) AF: 0.524 AC: 27715 AN: 52908

Middle Eastern (MID) AF: 0.453 AC: 2605 AN: 5752

European-Non Finnish (NFE) AF: 0.620 AC: 687384 AN: 1109052

Other (OTH) AF: 0.561 AC: 33817 AN: 60274

GnomAD4 genome AF: 0.509 AC: 77385 AN: 152014 Hom.: 20577 Cov.: 32 AF XY: 0.502 AC XY: 37294 AN XY: 74322

African (AFR) AF: 0.389 AC: 16130 AN: 41478

American (AMR) AF: 0.405 AC: 6184 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 1831 AN: 3466

East Asian (EAS) AF: 0.357 AC: 1844 AN: 5166

South Asian (SAS) AF: 0.609 AC: 2937 AN: 4824

European-Finnish (FIN) AF: 0.511 AC: 5384 AN: 10540

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.609 AC: 41403 AN: 67954

Other (OTH) AF: 0.512 AC: 1081 AN: 2112

Alfa AF: 0.544 Hom.: 19074

Bravo AF: 0.491

Asia WGS AF: 0.463 AC: 1608 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal dominant Parkinson disease 8 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.1
DANN	Benign	0.80
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

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: rs10878245; hg19: chr12-40631791; COSMIC: COSV54154315;