12-40319998-T-C

Variant names:

• chr12-40319998-T-C
• rs281865051
• NM_198578.4:c.4838T>C

Variant summary

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

The NM_198578.4(LRRK2):​c.4838T>C​(p.Val1613Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.57
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.4838T>C	p.Val1613Ala	missense	Exon 34 of 51	NP_940980.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.4838T>C	p.Val1613Ala	missense	Exon 34 of 51	ENSP00000298910.7
	LRRK2	ENST00000430804.5	TSL:1	n.*1511T>C		non_coding_transcript_exon	Exon 13 of 30	ENSP00000410821.1
	LRRK2	ENST00000430804.5	TSL:1	n.*1511T>C		3_prime_UTR	Exon 13 of 30	ENSP00000410821.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	0.0019
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.033	D
Polyphen		0.054	B
Vest4		0.52
MutPred		0.81		Gain of relative solvent accessibility (P = 0.0104)
MVP		0.75
MPC		0.12
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.31
gMVP		0.22
Mutation Taster		=69/31	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: rs281865051; hg19: chr12-40713800;