12-40320207-A-G

Position:

• chr12-40320207-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198578.4(LRRK2):​c.5015+32A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,527,296 control chromosomes in the GnomAD database, including 17,909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1918 hom., cov: 33)
  • Exomes 𝑓: 0.15 (15991 hom.)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.736

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]

LRRK2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-40320207-A-G is Benign according to our data. Variant chr12-40320207-A-G is described in ClinVar as [Benign]. Clinvar id is 1280855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.5015+32A>G		intron_variant		ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.5015+32A>G		intron_variant		1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22935 AN: 151914 Hom.: 1911 Cov.: 33

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0850

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.136

GnomAD3 exomes AF: 0.123 AC: 29814 AN: 242272 Hom.: 2217 AF XY: 0.127 AC XY: 16827 AN XY: 132612

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.0705

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.00115

Gnomad SAS exome AF: 0.165

Gnomad FIN exome AF: 0.0788

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.147 AC: 201878 AN: 1375264 Hom.: 15991 Cov.: 22 AF XY: 0.148 AC XY: 101692 AN XY: 689294

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.0754

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.00156

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.0865

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.140

GnomAD4 genome AF: 0.151 AC: 22977 AN: 152032 Hom.: 1918 Cov.: 33 AF XY: 0.147 AC XY: 10932 AN XY: 74336

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.0850

Gnomad4 NFE AF: 0.146

Gnomad4 OTH AF: 0.134

Alfa AF: 0.155 Hom.: 723

Bravo AF: 0.153

Asia WGS AF: 0.0880 AC: 307 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.027
DANN	Benign	0.76

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: rs11564205; hg19: chr12-40714009;