rs33962975

Positions:

• chr12-40363528-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198578.4(LRRK2):​c.7155A>G​(p.Gly2385=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,611,208 control chromosomes in the GnomAD database, including 16,076 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1252 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14824 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 1.34

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]

LOC105369736 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 12-40363528-A-G is Benign according to our data. Variant chr12-40363528-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 39234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40363528-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.7155A>G	p.Gly2385=	synonymous_variant	48/51	ENST00000298910.12
LOC105369736	XR_944868.3	n.485-8701T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.7155A>G	p.Gly2385=	synonymous_variant	48/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16574 AN: 151864 Hom.: 1250 Cov.: 32

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.0841

Gnomad ASJ AF: 0.0808

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.102

GnomAD3 exomes AF: 0.113 AC: 28221 AN: 250616 Hom.: 2177 AF XY: 0.112 AC XY: 15158 AN XY: 135478

Gnomad AFR exome AF: 0.0376

Gnomad AMR exome AF: 0.0745

Gnomad ASJ exome AF: 0.0810

Gnomad EAS exome AF: 0.0170

Gnomad SAS exome AF: 0.0368

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.134 AC: 195465 AN: 1459226 Hom.: 14824 Cov.: 34 AF XY: 0.132 AC XY: 95495 AN XY: 725966

Gnomad4 AFR exome AF: 0.0384

Gnomad4 AMR exome AF: 0.0742

Gnomad4 ASJ exome AF: 0.0811

Gnomad4 EAS exome AF: 0.0164

Gnomad4 SAS exome AF: 0.0364

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.109 AC: 16586 AN: 151982 Hom.: 1252 Cov.: 32 AF XY: 0.111 AC XY: 8278 AN XY: 74296

Gnomad4 AFR AF: 0.0411

Gnomad4 AMR AF: 0.0839

Gnomad4 ASJ AF: 0.0808

Gnomad4 EAS AF: 0.0165

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.256

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.101

Alfa AF: 0.124 Hom.: 833

Bravo AF: 0.0949

Asia WGS AF: 0.0380 AC: 131 AN: 3478

EpiCase AF: 0.140

EpiControl AF: 0.139

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 22, 2021	- -

not specified Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.0
DANN	Benign	0.62

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: rs33962975; hg19: chr12-40757330; COSMIC: COSV104599016;