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

Variant summary

Our verdict is Benign. Variant got -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

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 made for transcript

Verdict is Benign. Variant got -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 id 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

GnomAD3 exomes

AF:

0.0146

AC:

3632

AN:

249578

Hom.:

101

AF XY:

0.0131

AC XY:

1768

AN XY:

135404

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 SAS exome

AF:

0.00497

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

Gnomad4 AFR exome

AF:

0.0934

Gnomad4 AMR exome

AF:

0.0157

Gnomad4 ASJ exome

AF:

0.0461

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00524

Gnomad4 FIN exome

AF:

0.00178

Gnomad4 NFE exome

AF:

0.00754

Gnomad4 OTH exome

AF:

0.0174

GnomAD4 genome

AF:

0.0334

AC:

5082

AN:

152310

Hom.:

188

Cov.:

AF XY:

0.0324

AC XY:

2414

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0902

Gnomad4 AMR

AF:

0.0271

Gnomad4 ASJ

AF:

0.0513

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00856

Gnomad4 OTH

AF:

0.0340

Alfa

AF:

0.0210

Hom.:

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

DANN

Benign

0.37

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over