2-169204093-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004525.3(LRP2):c.7894A>G(p.Asn2632Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 1,614,116 control chromosomes in the GnomAD database, including 1,143 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 66 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1077 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.33

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028695464).

BP6

Variant 2-169204093-T-C is Benign according to our data. Variant chr2-169204093-T-C is described in ClinVar as [Benign]. Clinvar id is 129540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169204093-T-C is described in Lovd as [Benign]. Variant chr2-169204093-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0262 (3984/152252) while in subpopulation NFE AF= 0.0378 (2573/68002). AF 95% confidence interval is 0.0366. There are 66 homozygotes in gnomad4. There are 1970 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.7894A>G	p.Asn2632Asp	missense_variant	Exon 42 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.7894A>G	p.Asn2632Asp	missense_variant	Exon 42 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.6970A>G	p.Asn2324Asp	missense_variant	Exon 42 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.5605A>G	p.Asn1869Asp	missense_variant	Exon 27 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.7894A>G	p.Asn2632Asp	missense_variant	Exon 42 of 79		NM_004525.3	ENSP00000496870.1		P98164

Frequencies

GnomAD3 genomes

AF:

0.0262

AC:

3986

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00666

Gnomad AMI

AF:

0.0846

Gnomad AMR

AF:

0.0166

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.0158

Gnomad SAS

AF:

0.0280

Gnomad FIN

AF:

0.0452

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0379

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.0292

AC:

7349

AN:

251404

Hom.:

128

AF XY:

0.0306

AC XY:

4160

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00603

Gnomad AMR exome

AF:

0.0122

Gnomad ASJ exome

AF:

0.0227

Gnomad EAS exome

AF:

0.0140

Gnomad SAS exome

AF:

0.0333

Gnomad FIN exome

AF:

0.0434

Gnomad NFE exome

AF:

0.0369

Gnomad OTH exome

AF:

0.0318

GnomAD4 exome

AF:

0.0365

AC:

53385

AN:

1461864

Hom.:

1077

Cov.:

AF XY:

0.0366

AC XY:

26582

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00517

Gnomad4 AMR exome

AF:

0.0133

Gnomad4 ASJ exome

AF:

0.0197

Gnomad4 EAS exome

AF:

0.0142

Gnomad4 SAS exome

AF:

0.0336

Gnomad4 FIN exome

AF:

0.0414

Gnomad4 NFE exome

AF:

0.0399

Gnomad4 OTH exome

AF:

0.0320

GnomAD4 genome

AF:

0.0262

AC:

3984

AN:

152252

Hom.:

Cov.:

AF XY:

0.0265

AC XY:

1970

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00664

Gnomad4 AMR

AF:

0.0165

Gnomad4 ASJ

AF:

0.0202

Gnomad4 EAS

AF:

0.0158

Gnomad4 SAS

AF:

0.0280

Gnomad4 FIN

AF:

0.0452

Gnomad4 NFE

AF:

0.0378

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0323

Hom.:

151

Bravo

AF:

0.0233

TwinsUK

AF:

0.0461

AC:

171

ALSPAC

AF:

0.0400

AC:

154

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0374

AC:

322

ExAC

AF:

0.0295

AC:

3582

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0374

EpiControl

AF:

0.0358

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 10, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27197913, 19577669) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Donnai-Barrow syndrome

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.47

CADD

Benign

6.7

DANN

Benign

0.45

DEOGEN2

Benign

0.099

T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.39

.;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.98

L;L

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.7

.;N

REVEL

Benign

0.27

Sift

Benign

0.73

.;T

Sift4G

Benign

0.56

.;T

Polyphen

0.51

P;P

Vest4

0.043

MPC

0.27

ClinPred

0.0096

GERP RS

3.1

Varity_R

0.078

gMVP

0.41

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