rs41381646

Positions:

• chr15-101022426-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024652.6(LRRK1):​c.1896A>G​(p.Lys632=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.734

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]

ACMG classification

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/exons	MANE	UniProt
LRRK1	NM_024652.6	c.1896A>G	p.Lys632=	synonymous_variant	15/34	ENST00000388948.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK1	ENST00000388948.8	c.1896A>G	p.Lys632=	synonymous_variant	15/34	5	NM_024652.6	P1

Frequencies

GnomAD3 genomes AF: 0.0332 AC: 5058 AN: 152192 Hom.: 186 Cov.: 32

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

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.: 32 AF XY: 0.0102 AC XY: 7405 AN XY: 727248

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.: 32 AF XY: 0.0324 AC XY: 2414 AN XY: 74492

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.: 42

Bravo AF: 0.0382

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.00976

EpiControl AF: 0.0109

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LRRK1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

Other links and lift over

dbSNP: rs41381646; hg19: chr15-101562631;