chr15-100924710-T-C

Variant names:

• chr15-100924710-T-C
• rs11630691
• NM_024652.6:c.78T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.150
• Publications: 14 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

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.78T>C	p.Arg26Arg	synonymous	Exon 2 of 34	NP_078928.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK1	ENST00000388948.8	TSL:5 MANE Select	c.78T>C	p.Arg26Arg	synonymous	Exon 2 of 34	ENSP00000373600.3	Q38SD2-1
	LRRK1	ENST00000532029.6	TSL:1	c.78T>C	p.Arg26Arg	synonymous	Exon 2 of 6	ENSP00000433268.2	Q38SD2-2
	LRRK1	ENST00000525284.5	TSL:1	n.78T>C		non_coding_transcript_exon	Exon 1 of 33	ENSP00000433069.1	E9PMK9

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51526 AN: 151890 Hom.: 10927 Cov.: 32

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

GnomAD2 exomes AF: 0.255 AC: 63867 AN: 250810 AF XY: 0.255

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 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.: 32 AF XY: 0.264 AC XY: 191702 AN XY: 726822

African (AFR) AF: 0.621 AC: 20759 AN: 33446

American (AMR) AF: 0.140 AC: 6242 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 7870 AN: 26124

East Asian (EAS) AF: 0.126 AC: 4994 AN: 39698

South Asian (SAS) AF: 0.291 AC: 25111 AN: 86208

European-Finnish (FIN) AF: 0.214 AC: 11430 AN: 53410

Middle Eastern (MID) AF: 0.298 AC: 1713 AN: 5754

European-Non Finnish (NFE) AF: 0.261 AC: 290351 AN: 1111288

Other (OTH) AF: 0.281 AC: 16934 AN: 60358

GnomAD4 genome AF: 0.339 AC: 51603 AN: 152008 Hom.: 10949 Cov.: 32 AF XY: 0.331 AC XY: 24569 AN XY: 74298

African (AFR) AF: 0.601 AC: 24878 AN: 41414

American (AMR) AF: 0.223 AC: 3401 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1031 AN: 3464

East Asian (EAS) AF: 0.126 AC: 653 AN: 5178

South Asian (SAS) AF: 0.298 AC: 1434 AN: 4820

European-Finnish (FIN) AF: 0.193 AC: 2045 AN: 10584

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.254 AC: 17243 AN: 67960

Other (OTH) AF: 0.318 AC: 670 AN: 2108

Alfa AF: 0.285 Hom.: 9513

Bravo AF: 0.350

Asia WGS AF: 0.256 AC: 893 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.259

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	LRRK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.6
DANN	Benign	0.62
PhyloP100		-0.15
Mutation Taster		=296/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11630691; hg19: chr15-101464915; COSMIC: COSV52617349;