rs142549310

chr2-169173996-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_004525.3(LRP2):c.10937G>A(p.Arg3646His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,614,204 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.0028 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (12 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.36

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 Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRP2
• BP4: Computational evidence support a benign effect (MetaRNN=0.020164698).
• BP6: Variant 2-169173996-C-T is Benign according to our data. Variant chr2-169173996-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 74222.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=3}. Variant chr2-169173996-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00276 (421/152350) while in subpopulation NFE AF= 0.00365 (248/68038). AF 95% confidence interval is 0.00327. There are 3 homozygotes in gnomad4. There are 242 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.10937G>A	p.Arg3646His	missense_variant	56/79	ENST00000649046.1
LRP2	XM_011511183.4	c.10937G>A	p.Arg3646His	missense_variant	56/78
LRP2	XM_047444340.1	c.10013G>A	p.Arg3338His	missense_variant	56/79
LRP2	XM_011511184.3	c.8648G>A	p.Arg2883His	missense_variant	41/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.10937G>A	p.Arg3646His	missense_variant	56/79		NM_004525.3	P1
LRP2	ENST00000649153.1	c.1838G>A	p.Arg613His	missense_variant, NMD_transcript_variant	8/30
LRP2	ENST00000650252.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 421 AN: 152232 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00364

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00238 AC: 599 AN: 251368 Hom.: 1 AF XY: 0.00234 AC XY: 318 AN XY: 135850

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.00291

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00249 AC: 3634 AN: 1461854 Hom.: 12 Cov.: 32 AF XY: 0.00245 AC XY: 1783 AN XY: 727230

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0108

Gnomad4 NFE exome AF: 0.00262

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00276 AC: 421 AN: 152350 Hom.: 3 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74506

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0138

Gnomad4 NFE AF: 0.00365

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00289 Hom.: 2

Bravo AF: 0.00147

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00218 AC: 265

EpiCase AF: 0.00245

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	LRP2: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Donnai-Barrow syndrome Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 05, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

LRP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	13
Dann	Benign	0.96
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.82	D
MetaRNN	Benign	0.020	T;T
MetaSVM	Uncertain	0.033	D
MutationAssessor	Benign	0.89	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.19	T
Polyphen		0.30	B;B
Vest4		0.26
MVP		0.58
MPC		0.31
ClinPred		0.037	T
GERP RS		0.87
Varity_R		0.047
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs142549310; hg19: chr2-170030506; COSMIC: COSV55555211; COSMIC: COSV55555211;