2-169257160-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_004525.3(LRP2):c.2603C>G(p.Thr868Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000758 in 1,612,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in Lovd.

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 0 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 4.63

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0137916505).

BP6

Variant 2-169257160-G-C is Benign according to our data. Variant chr2-169257160-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129512.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}. Variant chr2-169257160-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00223 (340/152216) while in subpopulation AFR AF= 0.00609 (253/41552). AF 95% confidence interval is 0.00547. There are 0 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.2603C>G	p.Thr868Ser	missense_variant	Exon 18 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.2603C>G	p.Thr868Ser	missense_variant	Exon 18 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.1679C>G	p.Thr560Ser	missense_variant	Exon 18 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.314C>G	p.Thr105Ser	missense_variant	Exon 3 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.2603C>G	p.Thr868Ser	missense_variant	Exon 18 of 79		NM_004525.3	ENSP00000496870.1		P98164
LRP2	ENST00000443831.1 link	c.2192C>G	p.Thr731Ser	missense_variant	Exon 16 of 23	2		ENSP00000409813.1		E9PC35

Frequencies

GnomAD3 genomes

AF:

0.00223

AC:

339

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00608

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00348

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000324

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.000996

AC:

250

AN:

250886

Hom.:

AF XY:

0.000863

AC XY:

117

AN XY:

135566

show subpopulations

Gnomad AFR exome

AF:

0.00714

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000494

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000604

AC:

883

AN:

1460720

Hom.:

Cov.:

AF XY:

0.000582

AC XY:

423

AN XY:

726692

show subpopulations

Gnomad4 AFR exome

AF:

0.00652

Gnomad4 AMR exome

AF:

0.00188

Gnomad4 ASJ exome

AF:

0.000959

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000425

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.00223

AC:

340

AN:

152216

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

153

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00609

Gnomad4 AMR

AF:

0.00347

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000324

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.000762

Hom.:

Bravo

AF:

0.00325

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00104

AC:

126

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Jan 21, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30900415) -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 13, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Donnai-Barrow syndrome

Uncertain:1Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Intellectual disability

Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:1

Jun 16, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LRP2 c.2603C>G (p.Thr868Ser) results in a conservative amino acid change located in the LDLR class B repeat (IPR000033) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 282278 control chromosomes (gnomAD), predominantly at a frequency of 0.0064 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in LRP2 causing Donnai Barrow Syndrome (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2603C>G in individuals affected with Donnai Barrow Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014: four classified the variant as of uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

LRP2-related disorder

Benign:1

Apr 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

T;T;D

Eigen

Benign

-0.17

Eigen_PC

Benign

0.026

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.67

.;T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

0.12

N;N;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.4

.;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.17

.;T;T

Sift4G

Benign

0.12

.;T;T

Polyphen

0.0010

B;B;B

Vest4

0.30, 0.27

MVP

0.43

MPC

0.23

ClinPred

0.033

GERP RS

4.7

Varity_R

0.17

gMVP

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over