rs11175964

chr12-40309185-G-Achr12-40309185-G-C

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.4269G>A(p.Lys1423=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,613,646 control chromosomes in the GnomAD database, including 4,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (391 hom., cov: 32)
  • Exomes 𝑓: 0.069 (3898 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 1.22

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 12-40309185-G-A is Benign according to our data. Variant chr12-40309185-G-A is described in ClinVar as [Benign]. Clinvar id is 39181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40309185-G-A is described in Lovd as [Likely_benign]. Variant chr12-40309185-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.4269G>A	p.Lys1423=	synonymous_variant	30/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.4269G>A	p.Lys1423=	synonymous_variant	30/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.0603 AC: 9160 AN: 151992 Hom.: 391 Cov.: 32

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.0413

Gnomad FIN AF: 0.0546

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0686

Gnomad OTH AF: 0.0738

GnomAD3 exomes AF: 0.0746 AC: 18742 AN: 251084 Hom.: 877 AF XY: 0.0718 AC XY: 9743 AN XY: 135694

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.0878

Gnomad EAS exome AF: 0.0985

Gnomad SAS exome AF: 0.0399

Gnomad FIN exome AF: 0.0553

Gnomad NFE exome AF: 0.0721

Gnomad OTH exome AF: 0.0690

GnomAD4 exome AF: 0.0688 AC: 100604 AN: 1461536 Hom.: 3898 Cov.: 34 AF XY: 0.0678 AC XY: 49327 AN XY: 727060

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.0882

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.0392

Gnomad4 FIN exome AF: 0.0564

Gnomad4 NFE exome AF: 0.0684

Gnomad4 OTH exome AF: 0.0691

GnomAD4 genome AF: 0.0602 AC: 9158 AN: 152110 Hom.: 391 Cov.: 32 AF XY: 0.0612 AC XY: 4552 AN XY: 74362

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.0916

Gnomad4 EAS AF: 0.0995

Gnomad4 SAS AF: 0.0411

Gnomad4 FIN AF: 0.0546

Gnomad4 NFE AF: 0.0686

Gnomad4 OTH AF: 0.0720

Alfa AF: 0.0656 Hom.: 610

Bravo AF: 0.0645

Asia WGS AF: 0.0600 AC: 209 AN: 3478

EpiCase AF: 0.0701

EpiControl AF: 0.0670

ClinVar

Significance: 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	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	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 30, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	4.1
Dann	Benign	0.56

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: rs11175964; hg19: chr12-40702987; COSMIC: COSV54176653; COSMIC: COSV54176653;