2-169236027-C-G

Position:

• chr2-169236027-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_004525.3(LRP2):​c.4733G>C​(p.Arg1578Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1578C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.29

Genes affected

LRP2 (HGNC:6694): (LDL receptor related protein 2) The protein encoded by this gene, low density lipoprotein-related protein 2 (LRP2) or megalin, is a multi-ligand endocytic receptor that is expressed in many different tissues but primarily in absorptive epithilial tissues such as the kidney. This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain, and a short carboxy-terminal cytoplasmic tail. The extracellular ligand-binding-domains bind diverse macromolecules including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones. This protein also has a role in cell-signaling; extracellular ligands include parathyroid horomones and the morphogen sonic hedgehog while cytosolic ligands include MAP kinase scaffold proteins and JNK interacting proteins. Recycling of this membrane receptor is regulated by phosphorylation of its cytoplasmic domain. Mutations in this gene cause Donnai-Barrow syndrome (DBS) and facio-oculoacoustico-renal syndrome (FOAR).[provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LRP2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 2-169236027-C-G is Pathogenic according to our data. Variant chr2-169236027-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 437988.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-169236027-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.4733G>C	p.Arg1578Pro	missense_variant	29/79	ENST00000649046.1
LRP2	XM_011511183.4	c.4733G>C	p.Arg1578Pro	missense_variant	29/78
LRP2	XM_047444340.1	c.3809G>C	p.Arg1270Pro	missense_variant	29/79
LRP2	XM_011511184.3	c.2444G>C	p.Arg815Pro	missense_variant	14/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.4733G>C	p.Arg1578Pro	missense_variant	29/79		NM_004525.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinal dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.39	T
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.62		Gain of catalytic residue at P1577 (P = 0.0112);Gain of catalytic residue at P1577 (P = 0.0112);
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.91
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs111733491; hg19: chr2-170092537;