12-40267601-A-T

Variant names:

• chr12-40267601-A-T
• rs4768224
• NM_198578.4:c.1656+3700A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198578.4(LRRK2):​c.1656+3700A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 152,004 control chromosomes in the GnomAD database, including 38,622 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 0.71 (38622 hom., cov: 31)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.309
• Publications: 8 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: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198578.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.1656+3700A>T		intron	N/A	NP_940980.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.1656+3700A>T		intron	N/A	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000950031.1		c.1632+3700A>T		intron	N/A	ENSP00000620090.1
	LRRK2	ENST00000680790.1		c.1401+3700A>T		intron	N/A	ENSP00000505335.1	A0A7P0T8S1

Frequencies

GnomAD3 genomes AF: 0.711 AC: 108034 AN: 151886 Hom.: 38587 Cov.: 31

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.736

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.648

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.798

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.689

Gnomad OTH AF: 0.698

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

GnomAD4 genome AF: 0.711 AC: 108124 AN: 152004 Hom.: 38622 Cov.: 31 AF XY: 0.717 AC XY: 53265 AN XY: 74300

African (AFR) AF: 0.747 AC: 30968 AN: 41470

American (AMR) AF: 0.728 AC: 11100 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 2248 AN: 3468

East Asian (EAS) AF: 0.515 AC: 2652 AN: 5152

South Asian (SAS) AF: 0.736 AC: 3550 AN: 4826

European-Finnish (FIN) AF: 0.798 AC: 8445 AN: 10588

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.689 AC: 46843 AN: 67944

Other (OTH) AF: 0.694 AC: 1462 AN: 2108

Alfa AF: 0.711 Hom.: 4509

Bravo AF: 0.703

Asia WGS AF: 0.635 AC: 2208 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.6
DANN	Benign	0.52
PhyloP100		-0.31
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: rs4768224; hg19: chr12-40661403;