NM_198578.4:c.1383T>C

Variant names:

• chr12-40257342-T-C
• rs35847451
• NM_198578.4:c.1383T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_198578.4(LRRK2):​c.1383T>C​(p.Ser461Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,612,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.52
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-40257342-T-C is Benign according to our data. Variant chr12-40257342-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 695715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.52 with no splicing effect.
• BS2: High AC in GnomAd4 at 70 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.1383T>C	p.Ser461Ser	synonymous	Exon 12 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.1383T>C	p.Ser461Ser	synonymous	Exon 12 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000950031.1		c.1359T>C	p.Ser453Ser	synonymous	Exon 12 of 51	ENSP00000620090.1
	LRRK2	ENST00000343742.6	TSL:5	c.1383T>C	p.Ser461Ser	synonymous	Exon 12 of 27	ENSP00000341930.2	E9PC85

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000267 AC: 67 AN: 250796 AF XY: 0.000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.000495

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000266 AC: 388 AN: 1460670 Hom.: 0 Cov.: 30 AF XY: 0.000292 AC XY: 212 AN XY: 726710

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.0000671 AC: 3 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000324 AC: 360 AN: 1111252

Other (OTH) AF: 0.000116 AC: 7 AN: 60312

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.000131 AC: 2 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000911 AC: 62 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000610 Hom.: 0

Bravo AF: 0.000317

EpiCase AF: 0.000655

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal dominant Parkinson disease 8 (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	LRRK2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.2
DANN	Benign	0.75
PhyloP100		1.5
Mutation Taster		=100/0	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: rs35847451; hg19: chr12-40651144;