rs78154388

chr12-40277933-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_198578.4(LRRK2):c.1987T>C(p.Ser663Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,612,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 2.25

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20833102).
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.1987T>C	p.Ser663Pro	missense_variant	17/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.1987T>C	p.Ser663Pro	missense_variant	17/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 250458 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135418

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1460058 Hom.: 0 Cov.: 31 AF XY: 0.0000427 AC XY: 31 AN XY: 726394

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000902 Hom.: 0

Bravo AF: 0.0000189

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Uncertain:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 24, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	14
Dann	Uncertain	0.99
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.97	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.091
Sift	Benign	0.055	T;T;T
Sift4G	Uncertain	0.056	T;D;D
Polyphen		0.0020, 0.0	.;B;B
Vest4		0.28, 0.31
MutPred		0.41		.;Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);
MVP		0.83
MPC		0.11
ClinPred		0.15	T
GERP RS		2.5
Varity_R		0.28
gMVP		0.49

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: rs78154388; hg19: chr12-40671735;