12-40338592-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198578.4(LRRK2):c.5949-1702T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 152,144 control chromosomes in the GnomAD database, including 45,723 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.77 (45723 hom., cov: 33)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.170

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.5949-1702T>C		intron_variant		ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.5949-1702T>C		intron_variant		1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116766 AN: 152026 Hom.: 45699 Cov.: 33

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.737

Gnomad ASJ AF: 0.824

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.758

Gnomad FIN AF: 0.870

Gnomad MID AF: 0.834

Gnomad NFE AF: 0.855

Gnomad OTH AF: 0.774

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

GnomAD4 genome AF: 0.768 AC: 116842 AN: 152144 Hom.: 45723 Cov.: 33 AF XY: 0.767 AC XY: 57057 AN XY: 74382

Gnomad4 AFR AF: 0.618

Gnomad4 AMR AF: 0.737

Gnomad4 ASJ AF: 0.824

Gnomad4 EAS AF: 0.658

Gnomad4 SAS AF: 0.757

Gnomad4 FIN AF: 0.870

Gnomad4 NFE AF: 0.855

Gnomad4 OTH AF: 0.775

Alfa AF: 0.829 Hom.: 23869

Bravo AF: 0.749

Asia WGS AF: 0.673 AC: 2322 AN: 3448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	11
Dann	Benign	0.73

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: rs1427271; hg19: chr12-40732394;