2-169202833-C-A

Position:

• chr2-169202833-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004525.3(LRP2):​c.8132G>T​(p.Arg2711Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2711H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.100

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP2. . Trascript score misZ 4.5094 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, Stickler syndrome, Donnai-Barrow syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.8132G>T	p.Arg2711Leu	missense_variant	43/79	ENST00000649046.1
LRP2	XM_011511183.4	c.8132G>T	p.Arg2711Leu	missense_variant	43/78
LRP2	XM_047444340.1	c.7208G>T	p.Arg2403Leu	missense_variant	43/79
LRP2	XM_011511184.3	c.5843G>T	p.Arg1948Leu	missense_variant	28/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.8132G>T	p.Arg2711Leu	missense_variant	43/79		NM_004525.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	5.5
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;D
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.80	.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.18	T
PROVEAN	Pathogenic	-4.8	.;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.024	.;D
Sift4G	Uncertain	0.025	.;D
Polyphen		0.97	D;D
Vest4		0.26
MutPred		0.55		Loss of disorder (P = 0.0315);Loss of disorder (P = 0.0315);
MVP		0.47
MPC		0.81
ClinPred		0.99	D
GERP RS		-4.9
Varity_R		0.19
gMVP		0.45

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: rs190037522; hg19: chr2-170059343;