12-40346563-G-T

Position:

• chr12-40346563-G-T

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.6110-190G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 151,878 control chromosomes in the GnomAD database, including 7,274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.31 (7274 hom., cov: 32)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.938

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-40346563-G-T is Benign according to our data. Variant chr12-40346563-G-T is described in ClinVar as [Benign]. Clinvar id is 1257037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.6110-190G>T		intron_variant		ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.6110-190G>T		intron_variant		1	NM_198578.4	ENSP00000298910	P1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46312 AN: 151760 Hom.: 7272 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.288

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

GnomAD4 genome AF: 0.305 AC: 46330 AN: 151878 Hom.: 7274 Cov.: 32 AF XY: 0.310 AC XY: 23006 AN XY: 74222

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.281

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.341

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.391

Gnomad4 NFE AF: 0.325

Gnomad4 OTH AF: 0.290

Alfa AF: 0.227 Hom.: 593

Bravo AF: 0.291

Asia WGS AF: 0.345 AC: 1197 AN: 3478

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	Jul 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs10784522; hg19: chr12-40740365;