12-40315611-T-A

Position:

• chr12-40315611-T-A

Variant summary

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

The NM_198578.4(LRRK2):​c.4827+311T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 151,798 control chromosomes in the GnomAD database, including 37,320 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 0.70 (37320 hom., cov: 31)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01

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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.4827+311T>A		intron_variant		ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.4827+311T>A		intron_variant		1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes AF: 0.698 AC: 105879 AN: 151680 Hom.: 37285 Cov.: 31

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.713

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.781

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.674

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

GnomAD4 genome AF: 0.698 AC: 105972 AN: 151798 Hom.: 37320 Cov.: 31 AF XY: 0.704 AC XY: 52245 AN XY: 74180

Gnomad4 AFR AF: 0.769

Gnomad4 AMR AF: 0.713

Gnomad4 ASJ AF: 0.612

Gnomad4 EAS AF: 0.508

Gnomad4 SAS AF: 0.719

Gnomad4 FIN AF: 0.781

Gnomad4 NFE AF: 0.658

Gnomad4 OTH AF: 0.670

Alfa AF: 0.698 Hom.: 4603

Bravo AF: 0.691

Asia WGS AF: 0.633 AC: 2200 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.2
DANN	Benign	0.37

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: rs721709; hg19: chr12-40709413; COSMIC: COSV54156266;