rs150552608

chr2-169243501-G-Achr2-169243501-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004525.3(LRP2):c.3452C>T(p.Pro1151Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00662 in 1,614,060 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (104 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 7.07

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRP2
• BP4: Computational evidence support a benign effect (MetaRNN=0.004464656).
• BP6: Variant 2-169243501-G-A is Benign according to our data. Variant chr2-169243501-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169243501-G-A is described in Lovd as [Likely_benign]. Variant chr2-169243501-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1968/152262) while in subpopulation AFR AF= 0.0306 (1272/41530). AF 95% confidence interval is 0.0292. There are 22 homozygotes in gnomad4. There are 960 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.3452C>T	p.Pro1151Leu	missense_variant	23/79	ENST00000649046.1
LRP2	XM_011511183.4	c.3452C>T	p.Pro1151Leu	missense_variant	23/78
LRP2	XM_047444340.1	c.2528C>T	p.Pro843Leu	missense_variant	23/79
LRP2	XM_011511184.3	c.1163C>T	p.Pro388Leu	missense_variant	8/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.3452C>T	p.Pro1151Leu	missense_variant	23/79		NM_004525.3	P1
LRP2	ENST00000443831.1	c.3041C>T	p.Pro1014Leu	missense_variant	21/23	2

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1963 AN: 152144 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.00943

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.00413

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.00923 AC: 2322 AN: 251464 Hom.: 35 AF XY: 0.00934 AC XY: 1269 AN XY: 135910

Gnomad AFR exome AF: 0.0303

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.0361

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0195

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00539

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00596 AC: 8718 AN: 1461798 Hom.: 104 Cov.: 34 AF XY: 0.00649 AC XY: 4720 AN XY: 727202

Gnomad4 AFR exome AF: 0.0339

Gnomad4 AMR exome AF: 0.00570

Gnomad4 ASJ exome AF: 0.0344

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0187

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00356

Gnomad4 OTH exome AF: 0.0105

GnomAD4 genome AF: 0.0129 AC: 1968 AN: 152262 Hom.: 22 Cov.: 32 AF XY: 0.0129 AC XY: 960 AN XY: 74446

Gnomad4 AFR AF: 0.0306

Gnomad4 AMR AF: 0.00941

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0160

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00412

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.00688 Hom.: 14

Bravo AF: 0.0137

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.0275 AC: 121

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00992 AC: 1204

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.00862

EpiControl AF: 0.00907

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Donnai-Barrow syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2023	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;D;D
Eigen	Benign	-0.071
Eigen_PC	Benign	-0.066
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Uncertain	0.029	D
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.36	T
Polyphen		0.41	B;B;B
Vest4		0.45, 0.52
MVP		0.64
MPC		0.39
ClinPred		0.050	T
GERP RS		5.0
Varity_R		0.073
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150552608; hg19: chr2-170100011; COSMIC: COSV55558509;