rs587780383

chr2-169257145-T-C

Variant summary

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

The NM_004525.3(LRP2):c.2618A>G(p.Asn873Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000415 in 1,612,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.17

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 where missense usually causes diseases, LRP2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.2618A>G	p.Asn873Ser	missense_variant	18/79	ENST00000649046.1
LRP2	XM_011511183.4	c.2618A>G	p.Asn873Ser	missense_variant	18/78
LRP2	XM_047444340.1	c.1694A>G	p.Asn565Ser	missense_variant	18/79
LRP2	XM_011511184.3	c.329A>G	p.Asn110Ser	missense_variant	3/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.2618A>G	p.Asn873Ser	missense_variant	18/79		NM_004525.3	P1
LRP2	ENST00000443831.1	c.2207A>G	p.Asn736Ser	missense_variant	16/23	2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 250882 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135576

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000411 AC: 60 AN: 1460638 Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33 AN XY: 726658

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74316

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 13, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 07, 2022	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 873 of the LRP2 protein (p.Asn873Ser). This variant is present in population databases (rs587780383, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with LRP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 129513). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LRP2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T;D
Eigen	Benign	0.10
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.33	T
Polyphen		0.42	B;B;B
Vest4		0.47, 0.45
MutPred		0.58		Gain of glycosylation at N873 (P = 0.0072);Gain of glycosylation at N873 (P = 0.0072);.;
MVP		0.86
MPC		0.34
ClinPred		0.29	T
GERP RS		4.4
Varity_R		0.25
gMVP		0.80

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: rs587780383; hg19: chr2-170113655;