chr12-40224884-T-C

Position:

• chr12-40224884-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000416796.5(LRRK2):​c.-62-671T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 544,264 control chromosomes in the GnomAD database, including 462 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (372 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (90 hom.)
• Consequence: LRRK2 ENST00000416796.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.496

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-DT (HGNC:40848): (LRRK2 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-40224884-T-C is Benign according to our data. Variant chr12-40224884-T-C is described in ClinVar as [Benign]. Clinvar id is 1297877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000416796.5	c.-62-671T>C		intron_variant		3
LRRK2-DT	ENST00000618127.1	n.32A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 5905 AN: 152140 Hom.: 373 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.0268

GnomAD4 exome AF: 0.00429 AC: 1683 AN: 392018 Hom.: 90 Cov.: 4 AF XY: 0.00359 AC XY: 751 AN XY: 209208

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000246

Gnomad4 FIN exome AF: 0.0000806

Gnomad4 NFE exome AF: 0.000347

Gnomad4 OTH exome AF: 0.00930

GnomAD4 genome AF: 0.0389 AC: 5917 AN: 152246 Hom.: 372 Cov.: 32 AF XY: 0.0383 AC XY: 2854 AN XY: 74462

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0312 Hom.: 24

Bravo AF: 0.0445

Asia WGS AF: 0.00781 AC: 28 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.3
DANN	Benign	0.27

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs58621298; hg19: chr12-40618686;