12-40249854-C-T

Position:

• chr12-40249854-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000298910.12(LRRK2):​c.867C>T​(p.Asn289=) 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 ENST00000298910.12 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.18

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 308612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40249854-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1724 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.867C>T	p.Asn289=	synonymous_variant	8/51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.867C>T	p.Asn289=	synonymous_variant	8/51	1	NM_198578.4	ENSP00000298910	P1

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

GnomAD3 exomes AF: 0.00316 AC: 794 AN: 250970 Hom.: 16 AF XY: 0.00251 AC XY: 340 AN XY: 135624

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 SAS exome AF: 0.000229

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

Gnomad4 AFR exome AF: 0.0436

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000241

Gnomad4 OTH exome AF: 0.00333

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

Gnomad4 AFR AF: 0.0391

Gnomad4 AMR AF: 0.00452

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00387 Hom.: 6

Bravo AF: 0.0133

Asia WGS AF: 0.00404 AC: 14 AN: 3476

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 23, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.082
DANN	Benign	0.49

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: rs17490713; hg19: chr12-40643656;