12-40313976-G-A

Variant names:

• chr12-40313976-G-A
• rs35507033
• NM_198578.4:c.4541G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198578.4(LRRK2):​c.4541G>A​(p.Arg1514Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00695 in 1,609,956 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1514P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (59 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 5.84
• Publications: 37 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 (MetaRNN=0.009949774).
• BP6: Variant 12-40313976-G-A is Benign according to our data. Variant chr12-40313976-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 39191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00452 (686/151920) while in subpopulation NFE AF = 0.0076 (516/67932). AF 95% confidence interval is 0.00705. There are 1 homozygotes in GnomAd4. There are 321 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 686 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.4541G>A	p.Arg1514Gln	missense	Exon 32 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.4541G>A	p.Arg1514Gln	missense	Exon 32 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000430804.5	TSL:1	n.*1214G>A		non_coding_transcript_exon	Exon 11 of 30	ENSP00000410821.1	H7C3B6
	LRRK2	ENST00000430804.5	TSL:1	n.*1214G>A		3_prime_UTR	Exon 11 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes AF: 0.00453 AC: 687 AN: 151802 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00388

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00456

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00761

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00400 AC: 996 AN: 248880 AF XY: 0.00399

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00367

Gnomad NFE exome AF: 0.00688

Gnomad OTH exome AF: 0.00528

GnomAD4 exome AF: 0.00720 AC: 10496 AN: 1458036 Hom.: 59 Cov.: 31 AF XY: 0.00691 AC XY: 5012 AN XY: 725490

African (AFR) AF: 0.00129 AC: 43 AN: 33346

American (AMR) AF: 0.00211 AC: 94 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00211 AC: 55 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86158

European-Finnish (FIN) AF: 0.00392 AC: 205 AN: 52306

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5748

European-Non Finnish (NFE) AF: 0.00868 AC: 9635 AN: 1110096

Other (OTH) AF: 0.00751 AC: 452 AN: 60194

GnomAD4 genome AF: 0.00452 AC: 686 AN: 151920 Hom.: 1 Cov.: 32 AF XY: 0.00432 AC XY: 321 AN XY: 74264

African (AFR) AF: 0.00121 AC: 50 AN: 41446

American (AMR) AF: 0.00387 AC: 59 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00456 AC: 48 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00760 AC: 516 AN: 67932

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00616 Hom.: 8

Bravo AF: 0.00395

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00687 AC: 59

ExAC AF: 0.00373 AC: 453

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00753

EpiControl AF: 0.00647

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Autosomal dominant Parkinson disease 8 (4)
-	-	1	LRRK2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.025
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.52	N
PhyloP100		5.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.10
Sift	Benign	0.36	T
Sift4G	Benign	0.81	T
Polyphen		0.58	P
Vest4		0.39
MVP		0.83
MPC		0.21
ClinPred		0.012	T
GERP RS		5.0
Varity_R		0.25
gMVP		0.35
Mutation Taster		=89/11	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: rs35507033; hg19: chr12-40707778; COSMIC: COSV104599173;