chr12-40320071-A-G

Variant names:

• chr12-40320071-A-G
• rs11176013
• NM_198578.4:c.4911A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198578.4(LRRK2):​c.4911A>G​(p.Lys1637Lys) variant causes a synonymous change. The variant allele was found at a frequency of 0.558 in 1,608,610 control chromosomes in the GnomAD database, including 252,397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (24558 hom., cov: 32)
  • Exomes 𝑓: 0.56 (227839 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 4.58
• Publications: 45 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 12-40320071-A-G is Benign according to our data. Variant chr12-40320071-A-G is described in ClinVar as Benign. ClinVar VariationId is 39199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.675 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.4911A>G	p.Lys1637Lys	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.4911A>G	p.Lys1637Lys	synonymous	Exon 34 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000430804.5	TSL:1	n.*1584A>G		non_coding_transcript_exon	Exon 13 of 30	ENSP00000410821.1	H7C3B6
	LRRK2	ENST00000430804.5	TSL:1	n.*1584A>G		3_prime_UTR	Exon 13 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86053 AN: 151726 Hom.: 24541 Cov.: 32

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.630

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.557

GnomAD2 exomes AF: 0.576 AC: 143530 AN: 249074 AF XY: 0.576

Gnomad AFR exome AF: 0.586

Gnomad AMR exome AF: 0.664

Gnomad ASJ exome AF: 0.552

Gnomad EAS exome AF: 0.476

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.563

GnomAD4 exome AF: 0.557 AC: 810800 AN: 1456766 Hom.: 227839 Cov.: 37 AF XY: 0.560 AC XY: 405490 AN XY: 724696

African (AFR) AF: 0.587 AC: 19509 AN: 33252

American (AMR) AF: 0.659 AC: 29238 AN: 44372

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 14437 AN: 26044

East Asian (EAS) AF: 0.479 AC: 18942 AN: 39572

South Asian (SAS) AF: 0.688 AC: 58848 AN: 85532

European-Finnish (FIN) AF: 0.540 AC: 28800 AN: 53348

Middle Eastern (MID) AF: 0.502 AC: 2875 AN: 5728

European-Non Finnish (NFE) AF: 0.545 AC: 604358 AN: 1108706

Other (OTH) AF: 0.561 AC: 33793 AN: 60212

GnomAD4 genome AF: 0.567 AC: 86120 AN: 151844 Hom.: 24558 Cov.: 32 AF XY: 0.570 AC XY: 42262 AN XY: 74196

African (AFR) AF: 0.588 AC: 24370 AN: 41426

American (AMR) AF: 0.631 AC: 9614 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1918 AN: 3466

East Asian (EAS) AF: 0.482 AC: 2486 AN: 5162

South Asian (SAS) AF: 0.695 AC: 3356 AN: 4828

European-Finnish (FIN) AF: 0.531 AC: 5602 AN: 10542

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 37019 AN: 67876

Other (OTH) AF: 0.554 AC: 1168 AN: 2108

Alfa AF: 0.563 Hom.: 23219

Bravo AF: 0.571

Asia WGS AF: 0.591 AC: 2047 AN: 3472

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	-0.58
CADD	Benign	8.3
DANN	Benign	0.62
PhyloP100		4.6
Mutation Taster		=76/24	polymorphism

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: rs11176013; hg19: chr12-40713873; COSMIC: COSV54153519; COSMIC: COSV54153519;