rs7135747

Variant names:

• chr12-40252906-A-G
• rs7135747
• NM_198578.4:c.1182-4A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-40252906-A-G
• chr12-40252906-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198578.4(LRRK2):​c.1182-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,608,496 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (48 hom.)
• Consequence: LRRK2 NM_198578.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001860
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.123
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 12-40252906-A-G is Benign according to our data. Variant chr12-40252906-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 308614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2180/152334) while in subpopulation AFR AF = 0.0475 (1976/41574). AF 95% confidence interval is 0.0458. There are 45 homozygotes in GnomAd4. There are 973 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2180 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.1182-4A>G		splice_region intron	N/A	NP_940980.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.1182-4A>G		splice_region intron	N/A	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000950031.1		c.1158-4A>G		splice_region intron	N/A	ENSP00000620090.1
	LRRK2	ENST00000680790.1		c.1182-4A>G		splice_region intron	N/A	ENSP00000505335.1	A0A7P0T8S1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2181 AN: 152216 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00388 AC: 974 AN: 250846 AF XY: 0.00290

Gnomad AFR exome AF: 0.0467

Gnomad AMR exome AF: 0.00377

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00164 AC: 2381 AN: 1456162 Hom.: 48 Cov.: 29 AF XY: 0.00147 AC XY: 1069 AN XY: 724830

African (AFR) AF: 0.0497 AC: 1658 AN: 33330

American (AMR) AF: 0.00448 AC: 200 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00369 AC: 96 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5752

European-Non Finnish (NFE) AF: 0.000181 AC: 200 AN: 1107222

Other (OTH) AF: 0.00357 AC: 215 AN: 60172

GnomAD4 genome AF: 0.0143 AC: 2180 AN: 152334 Hom.: 45 Cov.: 32 AF XY: 0.0131 AC XY: 973 AN XY: 74480

African (AFR) AF: 0.0475 AC: 1976 AN: 41574

American (AMR) AF: 0.00954 AC: 146 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68032

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00604 Hom.: 31

Bravo AF: 0.0174

Asia WGS AF: 0.00289 AC: 10 AN: 3476

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.17
DANN	Benign	0.44
PhyloP100		0.12
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.094
SpliceAI score (max)		0.030		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: rs7135747; hg19: chr12-40646708;