12-40238297-T-G

Variant names:

• chr12-40238297-T-G
• rs10878246
• NM_198578.4:c.571+194T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198578.4(LRRK2):​c.571+194T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 152,114 control chromosomes in the GnomAD database, including 1,713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (1713 hom., cov: 32)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.76
• Publications: 10 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 12-40238297-T-G is Benign according to our data. Variant chr12-40238297-T-G is described in ClinVar as [Benign]. Clinvar id is 1272742.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.571+194T>G		intron_variant	Intron 5 of 50	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.571+194T>G		intron_variant	Intron 5 of 50	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21829 AN: 151996 Hom.: 1709 Cov.: 32

Gnomad AFR AF: 0.0971

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.138

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.144 AC: 21844 AN: 152114 Hom.: 1713 Cov.: 32 AF XY: 0.139 AC XY: 10351 AN XY: 74376

African (AFR) AF: 0.0972 AC: 4035 AN: 41516

American (AMR) AF: 0.112 AC: 1715 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 364 AN: 3468

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5182

South Asian (SAS) AF: 0.174 AC: 839 AN: 4822

European-Finnish (FIN) AF: 0.116 AC: 1224 AN: 10584

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13169 AN: 67962

Other (OTH) AF: 0.136 AC: 288 AN: 2112

Alfa AF: 0.176 Hom.: 3069

Bravo AF: 0.138

Asia WGS AF: 0.0800 AC: 278 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.58
CADD	Benign	14
DANN	Benign	0.81
PhyloP100		1.8
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: rs10878246; hg19: chr12-40632099;