Genetic Variant NM_024652.6:c.78T>C (chr15-100924710-T-C) – 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.78T>C(p.Arg26Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,612,990 control chromosomes in the GnomAD database, including 65,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 10949 hom., cov: 32)

Exomes 𝑓: 0.26 ( 54291 hom. )

Consequence

LRRK1
NM_024652.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.150

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=-0.85).

BP6

Variant 15-100924710-T-C is Benign according to our data. Variant chr15-100924710-T-C is described in ClinVar as [Benign]. Clinvar id is 1599963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.15 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK1	NM_024652.6 link	c.78T>C	p.Arg26Arg	synonymous_variant	Exon 2 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.78T>C	p.Arg26Arg	synonymous_variant	Exon 2 of 34	5	NM_024652.6	ENSP00000373600.3		Q38SD2-1

Frequencies

GnomAD3 genomes

AF:

0.339

AC:

51526

AN:

151890

Hom.:

10927

Cov.:

show subpopulations

Gnomad AFR

AF:

0.601

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.223

Gnomad ASJ

AF:

0.298

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.298

Gnomad FIN

AF:

0.193

Gnomad MID

AF:

0.283

Gnomad NFE

AF:

0.254

Gnomad OTH

AF:

0.314

GnomAD3 exomes

AF:

0.255

AC:

63867

AN:

250810

Hom.:

9858

AF XY:

0.255

AC XY:

34554

AN XY:

135598

show subpopulations

Gnomad AFR exome

AF:

0.619

Gnomad AMR exome

AF:

0.129

Gnomad ASJ exome

AF:

0.304

Gnomad EAS exome

AF:

0.119

Gnomad SAS exome

AF:

0.291

Gnomad FIN exome

AF:

0.210

Gnomad NFE exome

AF:

0.258

Gnomad OTH exome

AF:

0.244

GnomAD4 exome

AF:

0.264

AC:

385404

AN:

1460982

Hom.:

54291

Cov.:

AF XY:

0.264

AC XY:

191702

AN XY:

726822

show subpopulations

Gnomad4 AFR exome

AF:

0.621

Gnomad4 AMR exome

AF:

0.140

Gnomad4 ASJ exome

AF:

0.301

Gnomad4 EAS exome

AF:

0.126

Gnomad4 SAS exome

AF:

0.291

Gnomad4 FIN exome

AF:

0.214

Gnomad4 NFE exome

AF:

0.261

Gnomad4 OTH exome

AF:

0.281

GnomAD4 genome

AF:

0.339

AC:

51603

AN:

152008

Hom.:

10949

Cov.:

AF XY:

0.331

AC XY:

24569

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.601

Gnomad4 AMR

AF:

0.223

Gnomad4 ASJ

AF:

0.298

Gnomad4 EAS

AF:

0.126

Gnomad4 SAS

AF:

0.298

Gnomad4 FIN

AF:

0.193

Gnomad4 NFE

AF:

0.254

Gnomad4 OTH

AF:

0.318

Alfa

AF:

0.287

Hom.:

6579

Bravo

AF:

0.350

Asia WGS

AF:

0.256

AC:

893

AN:

3478

EpiCase

AF:

0.259

EpiControl

AF:

0.259

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 16, 2024

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

-0.85

CADD

Benign

4.6

DANN

Benign

0.62

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

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