rs34291900

Positions:

chr2-169273037-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004525.3(LRP2):c.2006G>A(p.Gly669Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0334 in 1,613,540 control chromosomes in the GnomAD database, including 1,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 62 hom., cov: 34)

Exomes 𝑓: 0.034 ( 978 hom. )

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 7.79

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:

LRP2 (HGNC:):

LRP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP2. . Trascript score misZ 4.5094 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, Stickler syndrome, Donnai-Barrow syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.012386203).

BP6

Variant 2-169273037-C-T is Benign according to our data. Variant chr2-169273037-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169273037-C-T is described in Lovd as [Benign]. Variant chr2-169273037-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0249 (3787/152260) while in subpopulation NFE AF= 0.0362 (2460/68026). AF 95% confidence interval is 0.035. There are 62 homozygotes in gnomad4. There are 1895 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 62 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3 linkuse as main transcript	c.2006G>A	p.Gly669Asp	missense_variant	15/79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 linkuse as main transcript	c.2006G>A	p.Gly669Asp	missense_variant	15/78		XP_011509485.1
LRP2	XM_047444340.1 linkuse as main transcript	c.1082G>A	p.Gly361Asp	missense_variant	15/79		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.2006G>A	p.Gly669Asp	missense_variant	15/79		NM_004525.3	ENSP00000496870.1	P98164
LRP2	ENST00000443831.1 linkuse as main transcript	c.1799G>A	p.Gly600Asp	missense_variant	14/23	2		ENSP00000409813.1	E9PC35
LRP2	ENST00000493501.1 linkuse as main transcript	n.349G>A		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes

AF:

0.0249

AC:

3790

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00572

Gnomad AMI

AF:

0.0505

Gnomad AMR

AF:

0.0202

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0274

Gnomad FIN

AF:

0.0455

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0362

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0280

AC:

7012

AN:

250820

Hom.:

140

AF XY:

0.0294

AC XY:

3979

AN XY:

135514

show subpopulations

Gnomad AFR exome

AF:

0.00566

Gnomad AMR exome

AF:

0.0133

Gnomad ASJ exome

AF:

0.0264

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0341

Gnomad FIN exome

AF:

0.0447

Gnomad NFE exome

AF:

0.0352

Gnomad OTH exome

AF:

0.0317

GnomAD4 exome

AF:

0.0343

AC:

50082

AN:

1461280

Hom.:

978

Cov.:

AF XY:

0.0345

AC XY:

25046

AN XY:

726948

show subpopulations

Gnomad4 AFR exome

AF:

0.00484

Gnomad4 AMR exome

AF:

0.0143

Gnomad4 ASJ exome

AF:

0.0232

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0340

Gnomad4 FIN exome

AF:

0.0431

Gnomad4 NFE exome

AF:

0.0373

Gnomad4 OTH exome

AF:

0.0304

GnomAD4 genome

AF:

0.0249

AC:

3787

AN:

152260

Hom.:

Cov.:

AF XY:

0.0255

AC XY:

1895

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00570

Gnomad4 AMR

AF:

0.0202

Gnomad4 ASJ

AF:

0.0222

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0274

Gnomad4 FIN

AF:

0.0455

Gnomad4 NFE

AF:

0.0362

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0317

Hom.:

129

Bravo

AF:

0.0217

TwinsUK

AF:

0.0421

AC:

156

ALSPAC

AF:

0.0368

AC:

142

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0352

AC:

303

ExAC

AF:

0.0285

AC:

3457

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0354

EpiControl

AF:

0.0336

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2020	This variant is associated with the following publications: (PMID: 21303902) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Donnai-Barrow syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;T;T

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

.;D;T

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Uncertain

2.7

M;M;.

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.4

.;D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0010

.;D;D

Sift4G

Pathogenic

0.0010

.;D;D

Polyphen

1.0

D;D;D

Vest4

0.86, 0.33

MPC

1.0

ClinPred

0.019

GERP RS

5.4

Varity_R

0.91

gMVP

0.76

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

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