Genetic Variant NM_024652.6:c.5652C>T (chr15-101066089-C-T) – 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.5652C>T(p.Pro1884Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00882 in 1,614,102 control chromosomes in the GnomAD database, including 922 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 498 hom., cov: 33)

Exomes 𝑓: 0.0051 ( 424 hom. )

Consequence

LRRK1
NM_024652.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.477

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:

LRRK1-AS1 (HGNC:58299):

LRRK1-AS1 links:

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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=-0.8).

BP6

Variant 15-101066089-C-T is Benign according to our data. Variant chr15-101066089-C-T is described in ClinVar as Benign. ClinVar VariationId is 1548827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.477 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024652.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK1	NM_024652.6	MANE Select	c.5652C>T	p.Pro1884Pro	synonymous	Exon 32 of 34	NP_078928.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRK1	ENST00000388948.8	TSL:5 MANE Select	c.5652C>T	p.Pro1884Pro	synonymous	Exon 32 of 34	ENSP00000373600.3	Q38SD2-1
LRRK1	ENST00000525284.5	TSL:1	n.*3778C>T		non_coding_transcript_exon	Exon 31 of 33	ENSP00000433069.1	E9PMK9
LRRK1	ENST00000526457.3	TSL:1	n.1680C>T		non_coding_transcript_exon	Exon 7 of 10	ENSP00000436672.2	H0YEW1

Frequencies

GnomAD3 genomes

AF:

0.0447

AC:

6799

AN:

152170

Hom.:

494

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0153

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.0345

GnomAD2 exomes

AF:

0.0119

AC:

2944

AN:

247866

AF XY:

0.00900

show subpopulations

Gnomad AFR exome

AF:

0.157

Gnomad AMR exome

AF:

0.00672

Gnomad ASJ exome

AF:

0.0155

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000716

Gnomad OTH exome

AF:

0.00611

GnomAD4 exome

AF:

0.00507

AC:

7408

AN:

1461814

Hom.:

424

Cov.:

AF XY:

0.00445

AC XY:

3239

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.160

AC:

5345

AN:

33480

American (AMR)

AF:

0.00762

AC:

341

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0158

AC:

413

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000499

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000487

AC:

542

AN:

1112010

Other (OTH)

AF:

0.0111

AC:

673

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

458

916

1375

1833

2291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

336

504

672

840

<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:

0.0448

AC:

6823

AN:

152288

Hom.:

498

Cov.:

AF XY:

0.0435

AC XY:

3243

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.154

AC:

6405

AN:

41540

American (AMR)

AF:

0.0153

AC:

234

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68038

Other (OTH)

AF:

0.0341

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

297

595

892

1190

1487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0236

Hom.:

173

Bravo

AF:

0.0508

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00124

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

LRRK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

9.4

(source)

DANN

Benign

0.45

PhyloP100

-0.48

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over