NM_198578.4:c.936G>T

Variant names:

• chr12-40249923-G-T
• rs41286466
• NM_198578.4:c.936G>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_198578.4(LRRK2):​c.936G>T​(p.Ala312Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,613,700 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A312A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (15 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -3.73
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 12-40249923-G-T is Benign according to our data. Variant chr12-40249923-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 39246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.73 with no splicing effect.
• BS2: High AC in GnomAd4 at 173 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.936G>T	p.Ala312Ala	synonymous	Exon 8 of 51	NP_940980.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.936G>T	p.Ala312Ala	synonymous	Exon 8 of 51	ENSP00000298910.7
	LRRK2	ENST00000680790.1		c.936G>T	p.Ala312Ala	synonymous	Exon 8 of 49	ENSP00000505335.1
	LRRK2	ENST00000343742.6	TSL:5	c.936G>T	p.Ala312Ala	synonymous	Exon 8 of 27	ENSP00000341930.2

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00180 AC: 451 AN: 250778 AF XY: 0.00204

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00169 AC: 2472 AN: 1461446 Hom.: 15 Cov.: 31 AF XY: 0.00184 AC XY: 1339 AN XY: 727032

African (AFR) AF: 0.000179 AC: 6 AN: 33454

American (AMR) AF: 0.000179 AC: 8 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00245 AC: 64 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00601 AC: 518 AN: 86246

European-Finnish (FIN) AF: 0.00208 AC: 111 AN: 53382

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5764

European-Non Finnish (NFE) AF: 0.00149 AC: 1656 AN: 1111750

Other (OTH) AF: 0.00156 AC: 94 AN: 60352

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152254 Hom.: 1 Cov.: 32 AF XY: 0.00120 AC XY: 89 AN XY: 74452

African (AFR) AF: 0.0000481 AC: 2 AN: 41544

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4824

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00182 AC: 124 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00126 Hom.: 1

Bravo AF: 0.000850

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00190

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal dominant Parkinson disease 8 (4)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.0040
DANN	Benign	0.42
PhyloP100		-3.7
Mutation Taster		=93/7	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: rs41286466; hg19: chr12-40643725; COSMIC: COSV54165288;