2-169257160-G-C

Variant names:

• chr2-169257160-G-C
• rs150752263
• NM_004525.3:c.2603C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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 ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T868N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (0 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 4.63
• Publications: 7 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: Benign. The variant received -9 ACMG points.

• 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 VariationId is 129512.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.2603C>G	p.Thr868Ser	missense	Exon 18 of 79	NP_004516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.2603C>G	p.Thr868Ser	missense	Exon 18 of 79	ENSP00000496870.1
	LRP2	ENST00000443831.1	TSL:2	c.2192C>G	p.Thr731Ser	missense	Exon 16 of 23	ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152098 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000996 AC: 250 AN: 250886 AF XY: 0.000863

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 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.: 0 Cov.: 32 AF XY: 0.000582 AC XY: 423 AN XY: 726692

African (AFR) AF: 0.00652 AC: 218 AN: 33426

American (AMR) AF: 0.00188 AC: 84 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.000959 AC: 25 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5754

European-Non Finnish (NFE) AF: 0.000425 AC: 472 AN: 1111204

Other (OTH) AF: 0.00124 AC: 75 AN: 60334

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00206 AC XY: 153 AN XY: 74432

African (AFR) AF: 0.00609 AC: 253 AN: 41552

American (AMR) AF: 0.00347 AC: 53 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67998

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.000762 Hom.: 0

Bravo AF: 0.00325

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00104 AC: 126

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

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

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)

Donnai-Barrow syndrome Uncertain:1 Benign: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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	0.12	N
PhyloP100		4.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.32
Sift	Benign	0.17	T
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.30
MVP		0.43
MPC		0.23
ClinPred		0.033	T
GERP RS		4.7
Varity_R		0.17
gMVP		0.39
Mutation Taster		=85/15	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: rs150752263; hg19: chr2-170113670; COSMIC: COSV104379429;