rs1427263

Variant names:

• chr12-40320032-C-A
• rs1427263
• NM_198578.4:c.4872C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-40320032-C-A
• chr12-40320032-C-G
• chr12-40320032-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_198578.4(LRRK2):​c.4872C>A​(p.Gly1624Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 1,608,450 control chromosomes in the GnomAD database, including 361,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37378 hom., cov: 32)
  • Exomes 𝑓: 0.66 (323642 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.535
• Publications: 47 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 12-40320032-C-A is Benign according to our data. Variant chr12-40320032-C-A is described in ClinVar as Benign. ClinVar VariationId is 39197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.535 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 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.4872C>A	p.Gly1624Gly	synonymous	Exon 34 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.4872C>A	p.Gly1624Gly	synonymous	Exon 34 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000430804.5	TSL:1	n.*1545C>A		non_coding_transcript_exon	Exon 13 of 30	ENSP00000410821.1	H7C3B6
	LRRK2	ENST00000430804.5	TSL:1	n.*1545C>A		3_prime_UTR	Exon 13 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106016 AN: 151782 Hom.: 37343 Cov.: 32

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.713

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.673

GnomAD2 exomes AF: 0.679 AC: 169662 AN: 249798 AF XY: 0.676

Gnomad AFR exome AF: 0.766

Gnomad AMR exome AF: 0.731

Gnomad ASJ exome AF: 0.610

Gnomad EAS exome AF: 0.502

Gnomad FIN exome AF: 0.777

Gnomad NFE exome AF: 0.656

Gnomad OTH exome AF: 0.673

GnomAD4 exome AF: 0.664 AC: 967676 AN: 1456552 Hom.: 323642 Cov.: 38 AF XY: 0.665 AC XY: 482154 AN XY: 724650

African (AFR) AF: 0.773 AC: 25738 AN: 33286

American (AMR) AF: 0.727 AC: 32391 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 15922 AN: 26024

East Asian (EAS) AF: 0.508 AC: 20120 AN: 39574

South Asian (SAS) AF: 0.719 AC: 61660 AN: 85760

European-Finnish (FIN) AF: 0.772 AC: 41214 AN: 53360

Middle Eastern (MID) AF: 0.605 AC: 3469 AN: 5734

European-Non Finnish (NFE) AF: 0.656 AC: 726807 AN: 1108084

Other (OTH) AF: 0.670 AC: 40355 AN: 60188

GnomAD4 genome AF: 0.699 AC: 106109 AN: 151898 Hom.: 37378 Cov.: 32 AF XY: 0.705 AC XY: 52334 AN XY: 74258

African (AFR) AF: 0.770 AC: 31909 AN: 41450

American (AMR) AF: 0.713 AC: 10866 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 2122 AN: 3466

East Asian (EAS) AF: 0.508 AC: 2619 AN: 5156

South Asian (SAS) AF: 0.720 AC: 3471 AN: 4824

European-Finnish (FIN) AF: 0.782 AC: 8261 AN: 10562

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44665 AN: 67894

Other (OTH) AF: 0.669 AC: 1410 AN: 2108

Alfa AF: 0.670 Hom.: 50932

Bravo AF: 0.691

Asia WGS AF: 0.633 AC: 2196 AN: 3474

EpiCase AF: 0.649

EpiControl AF: 0.644

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	-0.38
CADD	Benign	5.6
DANN	Benign	0.65
PhyloP100		0.54
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: rs1427263; hg19: chr12-40713834; COSMIC: COSV54146487;