rs190037522

Variant names:

• chr2-169202833-C-A
• rs190037522
• NM_004525.3:c.8132G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-169202833-C-A
• chr2-169202833-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

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
• Publications: 2 publications found

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]

LRP2 Gene-Disease associations (from GenCC):

• Donnai-Barrow syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Stickler syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.8132G>T	p.Arg2711Leu	missense_variant	Exon 43 of 79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.8132G>T	p.Arg2711Leu	missense_variant	Exon 43 of 78		XP_011509485.1
LRP2	XM_047444340.1	c.7208G>T	p.Arg2403Leu	missense_variant	Exon 43 of 79		XP_047300296.1
LRP2	XM_011511184.3	c.5843G>T	p.Arg1948Leu	missense_variant	Exon 28 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.8132G>T	p.Arg2711Leu	missense_variant	Exon 43 of 79		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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
PhyloP100		-0.10
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
Mutation Taster		=71/29	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: rs190037522; hg19: chr2-170059343;