NM_198578.4:c.867C>T

Variant names:

• chr12-40249854-C-T
• rs17490713
• NM_198578.4:c.867C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198578.4(LRRK2):​c.867C>T​(p.Asn289Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,613,648 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (43 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.18
• Publications: 7 publications found

Genes affected

LRRK2 (HGNC:18618): (leucine rich repeat kinase 2) This gene is a member of the leucine-rich repeat kinase family and encodes a protein with an ankryin repeat region, a leucine-rich repeat (LRR) domain, a kinase domain, a DFG-like motif, a RAS domain, a GTPase domain, a MLK-like domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Mutations in this gene have been associated with Parkinson disease-8. [provided by RefSeq, Jul 2008]

LRRK2 Gene-Disease associations (from GenCC):

• autosomal dominant Parkinson disease 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 12-40249854-C-T is Benign according to our data. Variant chr12-40249854-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 308612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1724/152178) while in subpopulation AFR AF = 0.0391 (1621/41506). AF 95% confidence interval is 0.0375. There are 39 homozygotes in GnomAd4. There are 820 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1724 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198578.4. 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
	LRRK2	NM_198578.4	MANE Select	c.867C>T	p.Asn289Asn	synonymous	Exon 8 of 51	NP_940980.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.867C>T	p.Asn289Asn	synonymous	Exon 8 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000950031.1		c.867C>T	p.Asn289Asn	synonymous	Exon 8 of 51	ENSP00000620090.1
	LRRK2	ENST00000680790.1		c.867C>T	p.Asn289Asn	synonymous	Exon 8 of 49	ENSP00000505335.1	A0A7P0T8S1

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1721 AN: 152060 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0391

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00316 AC: 794 AN: 250970 AF XY: 0.00251

Gnomad AFR exome AF: 0.0418

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.00141 AC: 2054 AN: 1461470 Hom.: 43 Cov.: 31 AF XY: 0.00129 AC XY: 937 AN XY: 727040

African (AFR) AF: 0.0436 AC: 1458 AN: 33448

American (AMR) AF: 0.00217 AC: 97 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86252

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53402

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5764

European-Non Finnish (NFE) AF: 0.000241 AC: 268 AN: 1111740

Other (OTH) AF: 0.00333 AC: 201 AN: 60358

GnomAD4 genome AF: 0.0113 AC: 1724 AN: 152178 Hom.: 39 Cov.: 32 AF XY: 0.0110 AC XY: 820 AN XY: 74406

African (AFR) AF: 0.0391 AC: 1621 AN: 41506

American (AMR) AF: 0.00452 AC: 69 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68016

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00411 Hom.: 8

Bravo AF: 0.0133

Asia WGS AF: 0.00404 AC: 14 AN: 3476

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal dominant Parkinson disease 8 (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.082
DANN	Benign	0.49
PhyloP100		-2.2
Mutation Taster		=97/3	polymorphism

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: rs17490713; hg19: chr12-40643656;