12-40225148-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198578.4(LRRK2):c.17G>A(p.Cys6Tyr) 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. 13/21 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. C6S) 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: 0.677

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.113108784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.17G>A	p.Cys6Tyr	missense_variant	1/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.17G>A	p.Cys6Tyr	missense_variant	1/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2022

The p.C6Y variant (also known as c.17G>A), located in coding exon 1 of the LRRK2 gene, results from a G to A substitution at nucleotide position 17. The cysteine at codon 6 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.024	T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.015	D;D
Sift4G	Benign	0.25	T;T
Polyphen		0.33	.;B
Vest4		0.21
MutPred		0.38		Gain of phosphorylation at C6 (P = 0.0833);Gain of phosphorylation at C6 (P = 0.0833);
MVP		0.73
MPC		0.17
ClinPred		0.47	T
GERP RS		4.7
Varity_R		0.40
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs1940800044; hg19: chr12-40618950;