rs34052957

Positions:

chr2-169207247-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1

The NM_004525.3(LRP2):c.6473A>C(p.Asn2158Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 1,612,820 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 7.99

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 -8 ACMG points.

PP2

Missense variant where missense usually causes diseases, LRP2

BP4

Computational evidence support a benign effect (MetaRNN=0.017685115).

BP6

Variant 2-169207247-T-G is Benign according to our data. Variant chr2-169207247-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 591104.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00149 (227/152250) while in subpopulation AFR AF= 0.00479 (199/41546). AF 95% confidence interval is 0.00424. There are 1 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRP2	NM_004525.3 linkuse as main transcript	c.6473A>C	p.Asn2158Thr	missense_variant	39/79	ENST00000649046.1
LRP2	XM_011511183.4 linkuse as main transcript	c.6473A>C	p.Asn2158Thr	missense_variant	39/78
LRP2	XM_047444340.1 linkuse as main transcript	c.5549A>C	p.Asn1850Thr	missense_variant	39/79
LRP2	XM_011511184.3 linkuse as main transcript	c.4184A>C	p.Asn1395Thr	missense_variant	24/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.6473A>C	p.Asn2158Thr	missense_variant	39/79		NM_004525.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

225

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00476

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000492

AC:

122

AN:

247810

Hom.:

AF XY:

0.000409

AC XY:

AN XY:

134386

show subpopulations

Gnomad AFR exome

AF:

0.00444

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00311

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000540

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000203

AC:

296

AN:

1460570

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

138

AN XY:

726672

show subpopulations

Gnomad4 AFR exome

AF:

0.00427

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00264

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.00149

AC:

227

AN:

152250

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

117

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00479

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000468

Hom.:

Bravo

AF:

0.00159

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000478

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2022	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27527004, 26934580, 27377421, 23675308) -
Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

LRP2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2022

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

Pathogenic

0.69

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.018

T;T

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

3.1

M;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.57

Polyphen

1.0

D;D

Vest4

0.90

MVP

0.81

MPC

0.87

ClinPred

0.049

GERP RS

6.0

Varity_R

0.74

gMVP

0.89

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