dbSNP rs17484286: LRRK2:c.3777+750A>G (chr12-40304884-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_198578.4(LRRK2):c.3777+750A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0814 in 152,130 control chromosomes in the GnomAD database, including 701 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 0.081 ( 701 hom., cov: 32)

Exomes 𝑓: 0.17 ( 0 hom. )

Consequence

LRRK2
NM_198578.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.150

Publications

6 publications found

Variant links:

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

LRRK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.3777+750A>G		intron_variant	Intron 27 of 50	ENST00000298910.12	NP_940980.4	Q5S007Q17RV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12 link	c.3777+750A>G		intron_variant	Intron 27 of 50	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.0814

AC:

12378

AN:

152000

Hom.:

700

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0201

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.0901

Gnomad ASJ

AF:

0.0958

Gnomad EAS

AF:

0.314

Gnomad SAS

AF:

0.0954

Gnomad FIN

AF:

0.0838

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0975

Gnomad OTH

AF:

0.0805

GnomAD4 exome

AF:

0.167

AC:

AN:

Hom.:

Cov.:

AF XY:

0.100

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.167

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0814

AC:

12383

AN:

152118

Hom.:

701

Cov.:

AF XY:

0.0818

AC XY:

6081

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0200

AC:

831

AN:

41556

American (AMR)

AF:

0.0903

AC:

1379

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0958

AC:

332

AN:

3466

East Asian (EAS)

AF:

0.314

AC:

1625

AN:

5172

South Asian (SAS)

AF:

0.0959

AC:

462

AN:

4820

European-Finnish (FIN)

AF:

0.0838

AC:

888

AN:

10596

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0975

AC:

6622

AN:

67914

Other (OTH)

AF:

0.0801

AC:

169

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

556

1113

1669

2226

2782

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0933

Hom.:

482

Bravo

AF:

0.0822

Asia WGS

AF:

0.201

AC:

698

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

2.8

(source)

DANN

Benign

0.37

PhyloP100

-0.15

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over