12-40304040-G-A

Variant names:

• chr12-40304040-G-A
• rs60185966
• NM_198578.4:c.3683G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198578.4(LRRK2):​c.3683G>A​(p.Ser1228Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1228I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.95
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15459573).

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.3683G>A	p.Ser1228Asn	missense	Exon 27 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.3683G>A	p.Ser1228Asn	missense	Exon 27 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000430804.5	TSL:1	n.*356G>A		non_coding_transcript_exon	Exon 6 of 30	ENSP00000410821.1	H7C3B6
	LRRK2	ENST00000430804.5	TSL:1	n.*356G>A		3_prime_UTR	Exon 6 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.9
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.15
Sift	Benign	0.39	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.53		Loss of sheet (P = 0.1158)
MVP		0.75
MPC		0.080
ClinPred		0.19	T
GERP RS		-0.14
Varity_R		0.064
gMVP		0.45
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs60185966; hg19: chr12-40697842;