12-40320207-A-G

Variant names:

• chr12-40320207-A-G
• rs11564205
• NM_198578.4:c.5015+32A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant Parkinson disease 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258167 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.5015+32A>G		intron_variant	Intron 34 of 50	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.5015+32A>G		intron_variant	Intron 34 of 50	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

GnomAD2 exomes AF: 0.123 AC: 29814 AN: 242272 AF XY: 0.127

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 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

African (AFR) AF: 0.215 AC: 6808 AN: 31596

American (AMR) AF: 0.0754 AC: 3337 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3032 AN: 25484

East Asian (EAS) AF: 0.00156 AC: 61 AN: 39136

South Asian (SAS) AF: 0.167 AC: 14071 AN: 84026

European-Finnish (FIN) AF: 0.0865 AC: 4529 AN: 52336

Middle Eastern (MID) AF: 0.109 AC: 539 AN: 4932

European-Non Finnish (NFE) AF: 0.156 AC: 161468 AN: 1036164

Other (OTH) AF: 0.140 AC: 8033 AN: 57356

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

African (AFR) AF: 0.214 AC: 8878 AN: 41444

American (AMR) AF: 0.106 AC: 1612 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 396 AN: 3470

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5192

South Asian (SAS) AF: 0.162 AC: 779 AN: 4822

European-Finnish (FIN) AF: 0.0850 AC: 902 AN: 10606

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9942 AN: 67936

Other (OTH) AF: 0.134 AC: 283 AN: 2110

Alfa AF: 0.155 Hom.: 736

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.027
DANN	Benign	0.76
PhyloP100		-0.74
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11564205; hg19: chr12-40714009;