chr12-40293624-G-C

Position:

• chr12-40293624-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_198578.4(LRRK2):​c.2769G>C​(p.Gln923His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,611,608 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2 O:1
• Conservation: PhyloP100: 0.0930

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1672214).
• BP6: Variant 12-40293624-G-C is Benign according to our data. Variant chr12-40293624-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39153.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.2769G>C	p.Gln923His	missense_variant	21/51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.2769G>C	p.Gln923His	missense_variant	21/51	1	NM_198578.4	ENSP00000298910	P1
LRRK2	ENST00000680790.1	c.2514G>C	p.Gln838His	missense_variant	19/49			ENSP00000505335
LRRK2	ENST00000343742.6	c.2769G>C	p.Gln923His	missense_variant	21/27	5		ENSP00000341930
LRRK2	ENST00000679360.1	c.*1678G>C		3_prime_UTR_variant, NMD_transcript_variant	22/51			ENSP00000505368

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151846 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000199 AC: 50 AN: 250650 Hom.: 0 AF XY: 0.000207 AC XY: 28 AN XY: 135504

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000139 AC: 203 AN: 1459646 Hom.: 1 Cov.: 29 AF XY: 0.000145 AC XY: 105 AN XY: 726156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000785

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151962 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74268

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	LRRK2: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2017	The Q923H variant in the LRRK2 gene has been reported previously in families with autosomal dominant Parkinson disease, however it was not found to segregate with disease in these families (Camargos et al., 2009; Jasinska-Myga et al., 2010). The Q923H variant has also been reported in individuals with sporadic Parkinson disease, however it is also seen at a similar frequency in control subjects (Jasinska-Myga et al., 2010; Ross et al., 2011). The Q923H variant is observed in 7/11236 (0.06%) alleles from individuals of Latino background, in the ExAC dataset (Lek et al., 2016). The Q923H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret Q923H as a variant of uncertain significance. -

Autosomal dominant Parkinson disease 8 Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 24, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.81
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.3	.;M
MutationTaster	Benign	0.89	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.27
Sift	Benign	0.047	D;D
Sift4G	Uncertain	0.045	D;T
Polyphen		0.99	D;D
Vest4		0.47
MutPred		0.35		Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);
MVP		0.79
MPC		0.38
ClinPred		0.092	T
GERP RS		-1.9
Varity_R		0.072
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs58559150; hg19: chr12-40687426;