12-40319957-T-C

Variant names:

• chr12-40319957-T-C
• rs1896252
• NM_198578.4:c.4828-31T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198578.4(LRRK2):​c.4828-31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 1,574,482 control chromosomes in the GnomAD database, including 245,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (24538 hom., cov: 31)
  • Exomes 𝑓: 0.55 (221229 hom.)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0240
• Publications: 17 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• Parkinson disease

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258167 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-40319957-T-C is Benign according to our data. Variant chr12-40319957-T-C is described in ClinVar as Benign. ClinVar VariationId is 1287923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.4828-31T>C		intron_variant	Intron 33 of 50	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.4828-31T>C		intron_variant	Intron 33 of 50	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes AF: 0.567 AC: 85988 AN: 151626 Hom.: 24521 Cov.: 31

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.631

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.697

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.558

GnomAD2 exomes AF: 0.573 AC: 135063 AN: 235710 AF XY: 0.572

Gnomad AFR exome AF: 0.586

Gnomad AMR exome AF: 0.658

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.475

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.563

GnomAD4 exome AF: 0.555 AC: 789273 AN: 1422738 Hom.: 221229 Cov.: 25 AF XY: 0.558 AC XY: 395315 AN XY: 708692

African (AFR) AF: 0.587 AC: 18547 AN: 31608

American (AMR) AF: 0.654 AC: 26025 AN: 39782

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 13913 AN: 25218

East Asian (EAS) AF: 0.478 AC: 18845 AN: 39388

South Asian (SAS) AF: 0.687 AC: 56273 AN: 81852

European-Finnish (FIN) AF: 0.540 AC: 28639 AN: 53038

Middle Eastern (MID) AF: 0.502 AC: 2656 AN: 5290

European-Non Finnish (NFE) AF: 0.544 AC: 591414 AN: 1087720

Other (OTH) AF: 0.560 AC: 32961 AN: 58842

GnomAD4 genome AF: 0.567 AC: 86055 AN: 151744 Hom.: 24538 Cov.: 31 AF XY: 0.569 AC XY: 42219 AN XY: 74146

African (AFR) AF: 0.588 AC: 24352 AN: 41406

American (AMR) AF: 0.632 AC: 9596 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1917 AN: 3464

East Asian (EAS) AF: 0.481 AC: 2483 AN: 5164

South Asian (SAS) AF: 0.695 AC: 3352 AN: 4820

European-Finnish (FIN) AF: 0.531 AC: 5600 AN: 10554

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 36998 AN: 67834

Other (OTH) AF: 0.555 AC: 1169 AN: 2106

Alfa AF: 0.562 Hom.: 8404

Bravo AF: 0.571

Asia WGS AF: 0.592 AC: 2054 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.8
DANN	Benign	0.74
PhyloP100		0.024
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1896252; hg19: chr12-40713759; COSMIC: COSV54144449;