rs2256408

chr12-40225280-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198578.4(LRRK2):c.149G>A(p.Arg50His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,614,078 control chromosomes in the GnomAD database, including 799,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.97 (72070 hom., cov: 31)
  • Exomes 𝑓: 1.0 (726959 hom.)
• Consequence: LRRK2 NM_198578.4 missense, splice_region
• Scores: Splicing: ADA: 0.00004042
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 0.216

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.569986E-7).
• BP6: Variant 12-40225280-G-A is Benign according to our data. Variant chr12-40225280-G-A is described in ClinVar as [Benign]. Clinvar id is 1169383.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-40225280-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.149G>A	p.Arg50His	missense_variant, splice_region_variant	1/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.149G>A	p.Arg50His	missense_variant, splice_region_variant	1/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.972 AC: 147895 AN: 152150 Hom.: 72012 Cov.: 31

Gnomad AFR AF: 0.902

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.991

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.978

GnomAD3 exomes AF: 0.993 AC: 249243 AN: 251046 Hom.: 123794 AF XY: 0.995 AC XY: 135044 AN XY: 135766

Gnomad AFR exome AF: 0.898

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.997 AC: 1457662 AN: 1461810 Hom.: 726959 Cov.: 52 AF XY: 0.998 AC XY: 725432 AN XY: 727210

Gnomad4 AFR exome AF: 0.896

Gnomad4 AMR exome AF: 0.996

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.994

GnomAD4 genome AF: 0.972 AC: 148011 AN: 152268 Hom.: 72070 Cov.: 31 AF XY: 0.972 AC XY: 72363 AN XY: 74436

Gnomad4 AFR AF: 0.902

Gnomad4 AMR AF: 0.991

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.978

Alfa AF: 0.995 Hom.: 144882

Bravo AF: 0.969

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.899 AC: 3959

ESP6500EA AF: 1.00 AC: 8598

ExAC AF: 0.991 AC: 120325

Asia WGS AF: 0.995 AC: 3459 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal dominant Parkinson disease 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	12
Dann	Benign	0.82
DEOGEN2	Benign	0.023	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0035	N
LIST_S2	Benign	0.16	T;T
MetaRNN	Benign	8.6e-7	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.63	N;N
REVEL	Benign	0.029
Sift	Benign	1.0	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.0	.;B
Vest4		0.014
MPC		0.11
ClinPred		0.0031	T
GERP RS		-1.3
Varity_R		0.025
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.0
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: rs2256408; hg19: chr12-40619082;