dbSNP rs41381646: LRRK1:p.Lys632Lys (chr15-101022426-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

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

The NM_024652.6(LRRK1):c.1896A>G(p.Lys632Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,202 control chromosomes in the GnomAD database, including 418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 188 hom., cov: 32)

Exomes 𝑓: 0.010 ( 230 hom. )

Consequence

LRRK1
NM_024652.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.734

Publications

2 publications found

Variant links:

Genes affected

LRRK1 (HGNC:18608): (leucine rich repeat kinase 1) This gene encodes a multi-domain protein that is a leucine-rich repeat kinase and a GDP/GTP binding protein. The encoded protein is thought to play a role in the regulation of bone mass. Mice lacking a similar gene showed severe osteopetrosis, increased bone mineralization and decreased bone resorption. [provided by RefSeq, Jan 2017]

LRRK1 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=-0.84).

BP6

Variant 15-101022426-A-G is Benign according to our data. Variant chr15-101022426-A-G is described in ClinVar as Benign. ClinVar VariationId is 1654890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.734 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK1	NM_024652.6 link	c.1896A>G	p.Lys632Lys	synonymous_variant	Exon 15 of 34	ENST00000388948.8	NP_078928.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK1	ENST00000388948.8 link	c.1896A>G	p.Lys632Lys	synonymous_variant	Exon 15 of 34	5	NM_024652.6	ENSP00000373600.3		Q38SD2-1

Frequencies

GnomAD3 genomes

AF:

0.0332

AC:

5058

AN:

152192

Hom.:

186

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0899

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0272

Gnomad ASJ

AF:

0.0513

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00855

Gnomad OTH

AF:

0.0344

GnomAD2 exomes

AF:

0.0146

AC:

3632

AN:

249578

AF XY:

0.0131

show subpopulations

Gnomad AFR exome

AF:

0.0954

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.0449

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.00801

Gnomad OTH exome

AF:

0.0162

GnomAD4 exome

AF:

0.0104

AC:

15154

AN:

1461892

Hom.:

230

Cov.:

AF XY:

0.0102

AC XY:

7405

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0934

AC:

3126

AN:

33480

American (AMR)

AF:

0.0157

AC:

702

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0461

AC:

1206

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00524

AC:

452

AN:

86258

European-Finnish (FIN)

AF:

0.00178

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0241

AC:

139

AN:

5768

European-Non Finnish (NFE)

AF:

0.00754

AC:

8381

AN:

1112012

Other (OTH)

AF:

0.0174

AC:

1052

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

831

1662

2493

3324

4155

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

386

772

1158

1544

1930

<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:

0.0334

AC:

5082

AN:

152310

Hom.:

188

Cov.:

AF XY:

0.0324

AC XY:

2414

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0902

AC:

3747

AN:

41554

American (AMR)

AF:

0.0271

AC:

415

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0513

AC:

178

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00332

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00856

AC:

582

AN:

68028

Other (OTH)

AF:

0.0340

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

238

476

714

952

1190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0198

Hom.:

188

Bravo

AF:

0.0382

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00976

EpiControl

AF:

0.0109

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

LRRK1-related disorder

Benign:1

May 01, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.8

(source)

DANN

Benign

0.37

PhyloP100

-0.73

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over