12-40322458-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_198578.4(LRRK2):c.5457T>C(p.Gly1819Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,612,358 control chromosomes in the GnomAD database, including 252,740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1819G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.57 ( 24464 hom., cov: 31)

Exomes 𝑓: 0.56 ( 228276 hom. )

Consequence

LRRK2
NM_198578.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -0.506

Publications

40 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: 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

LRRK2 links:

ENSG00000258167 (HGNC:):

ENSG00000258167 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 12-40322458-T-C is Benign according to our data. Variant chr12-40322458-T-C is described in ClinVar as Benign. ClinVar VariationId is 39209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.506 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.676 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.5457T>C	p.Gly1819Gly	synonymous	Exon 37 of 51	NP_940980.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.5457T>C	p.Gly1819Gly	synonymous	Exon 37 of 51	ENSP00000298910.7	Q5S007
LRRK2	ENST00000430804.5	TSL:1	n.*2130T>C		non_coding_transcript_exon	Exon 16 of 30	ENSP00000410821.1	H7C3B6
LRRK2	ENST00000430804.5	TSL:1	n.*2130T>C		3_prime_UTR	Exon 16 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes

AF:

0.566

AC:

85848

AN:

151542

Hom.:

24447

Cov.:

show subpopulations

Gnomad AFR

AF:

0.587

Gnomad AMI

AF:

0.487

Gnomad AMR

AF:

0.630

Gnomad ASJ

AF:

0.553

Gnomad EAS

AF:

0.481

Gnomad SAS

AF:

0.696

Gnomad FIN

AF:

0.530

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.545

Gnomad OTH

AF:

0.557

GnomAD2 exomes

AF:

0.577

AC:

144889

AN:

251196

AF XY:

0.577

show subpopulations

Gnomad AFR exome

AF:

0.586

Gnomad AMR exome

AF:

0.664

Gnomad ASJ exome

AF:

0.553

Gnomad EAS exome

AF:

0.477

Gnomad FIN exome

AF:

0.536

Gnomad NFE exome

AF:

0.545

Gnomad OTH exome

AF:

0.564

GnomAD4 exome

AF:

0.557

AC:

813102

AN:

1460698

Hom.:

228276

Cov.:

AF XY:

0.560

AC XY:

406709

AN XY:

726706

show subpopulations

African (AFR)

AF:

0.586

AC:

19590

AN:

33456

American (AMR)

AF:

0.659

AC:

29476

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.554

AC:

14474

AN:

26106

East Asian (EAS)

AF:

0.479

AC:

18979

AN:

39630

South Asian (SAS)

AF:

0.688

AC:

59347

AN:

86218

European-Finnish (FIN)

AF:

0.540

AC:

28831

AN:

53396

Middle Eastern (MID)

AF:

0.502

AC:

2893

AN:

5762

European-Non Finnish (NFE)

AF:

0.545

AC:

605644

AN:

1111066

Other (OTH)

AF:

0.561

AC:

33868

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

18945

37890

56834

75779

94724

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17164

34328

51492

68656

85820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.566

AC:

85915

AN:

151660

Hom.:

24464

Cov.:

AF XY:

0.569

AC XY:

42136

AN XY:

74094

show subpopulations

African (AFR)

AF:

0.587

AC:

24314

AN:

41420

American (AMR)

AF:

0.630

AC:

9593

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.553

AC:

1916

AN:

3462

East Asian (EAS)

AF:

0.480

AC:

2473

AN:

5148

South Asian (SAS)

AF:

0.695

AC:

3351

AN:

4820

European-Finnish (FIN)

AF:

0.530

AC:

5569

AN:

10508

Middle Eastern (MID)

AF:

0.490

AC:

144

AN:

294

European-Non Finnish (NFE)

AF:

0.545

AC:

36940

AN:

67770

Other (OTH)

AF:

0.555

AC:

1171

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1871

3742

5613

7484

9355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

734

1468

2202

2936

3670

<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:

0.553

Hom.:

17190

Bravo

AF:

0.570

Asia WGS

AF:

0.590

AC:

2048

AN:

3478

EpiCase

AF:

0.540

EpiControl

AF:

0.536

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Autosomal dominant Parkinson disease 8 (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.3

(source)

DANN

Benign

0.67

PhyloP100

-0.51

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over