rs2412000

chr15-100989389-G-Achr15-100989389-G-C

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.753G>A(p.Pro251=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.065 in 1,613,942 control chromosomes in the GnomAD database, including 6,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2430 hom., cov: 33)
  • Exomes 𝑓: 0.058 (4147 hom.)
• Consequence: LRRK1 NM_024652.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.99

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=-0.81).
• BP6: Variant 15-100989389-G-A is Benign according to our data. Variant chr15-100989389-G-A is described in ClinVar as [Benign]. Clinvar id is 1636917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK1	NM_024652.6	c.753G>A	p.Pro251=	synonymous_variant	6/34	ENST00000388948.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK1	ENST00000388948.8	c.753G>A	p.Pro251=	synonymous_variant	6/34	5	NM_024652.6	P1
LRRK1	ENST00000532029.6	c.753G>A	p.Pro251=	synonymous_variant	6/6	1
LRRK1	ENST00000525284.5	c.753G>A	p.Pro251=	synonymous_variant, NMD_transcript_variant	5/33	1
LRRK1	ENST00000531270.5	c.753G>A	p.Pro251=	synonymous_variant, NMD_transcript_variant	5/32	1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19305 AN: 152112 Hom.: 2423 Cov.: 33

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0768

Gnomad ASJ AF: 0.0640

Gnomad EAS AF: 0.00807

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.0294

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0503

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.0645 AC: 16091 AN: 249476 Hom.: 1190 AF XY: 0.0615 AC XY: 8318 AN XY: 135340

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.0453

Gnomad ASJ exome AF: 0.0715

Gnomad EAS exome AF: 0.00578

Gnomad SAS exome AF: 0.0641

Gnomad FIN exome AF: 0.0265

Gnomad NFE exome AF: 0.0486

Gnomad OTH exome AF: 0.0589

GnomAD4 exome AF: 0.0585 AC: 85494 AN: 1461712 Hom.: 4147 Cov.: 32 AF XY: 0.0580 AC XY: 42142 AN XY: 727158

Gnomad4 AFR exome AF: 0.344

Gnomad4 AMR exome AF: 0.0501

Gnomad4 ASJ exome AF: 0.0683

Gnomad4 EAS exome AF: 0.0109

Gnomad4 SAS exome AF: 0.0612

Gnomad4 FIN exome AF: 0.0280

Gnomad4 NFE exome AF: 0.0519

Gnomad4 OTH exome AF: 0.0742

GnomAD4 genome AF: 0.127 AC: 19357 AN: 152230 Hom.: 2430 Cov.: 33 AF XY: 0.123 AC XY: 9132 AN XY: 74436

Gnomad4 AFR AF: 0.329

Gnomad4 AMR AF: 0.0766

Gnomad4 ASJ AF: 0.0640

Gnomad4 EAS AF: 0.00809

Gnomad4 SAS AF: 0.0530

Gnomad4 FIN AF: 0.0294

Gnomad4 NFE AF: 0.0503

Gnomad4 OTH AF: 0.113

Alfa AF: 0.0725 Hom.: 973

Bravo AF: 0.140

Asia WGS AF: 0.0660 AC: 231 AN: 3478

EpiCase AF: 0.0538

EpiControl AF: 0.0540

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

Apr 09, 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	-0.81
Cadd	Benign	0.038
Dann	Benign	0.44

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

Other links and lift over

dbSNP: rs2412000; hg19: chr15-101529594;