NM_004525.3:c.639C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_004525.3(LRP2):c.639C>T(p.Asp213Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.28 in 1,602,868 control chromosomes in the GnomAD database, including 66,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7473 hom., cov: 31)

Exomes 𝑓: 0.28 ( 59287 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.09

Publications

25 publications found

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 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

LRP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 2-169294161-G-A is Benign according to our data. Variant chr2-169294161-G-A is described in ClinVar as [Benign]. Clinvar id is 129533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.639C>T	p.Asp213Asp	synonymous_variant	Exon 6 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_047444340.1 link	c.-286C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 6 of 79		XP_047300296.1
LRP2	XM_011511183.4 link	c.639C>T	p.Asp213Asp	synonymous_variant	Exon 6 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.-286C>T		5_prime_UTR_variant	Exon 6 of 79		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.639C>T	p.Asp213Asp	synonymous_variant	Exon 6 of 79		NM_004525.3	ENSP00000496870.1		P98164
LRP2	ENST00000443831.1 link	c.639C>T	p.Asp213Asp	synonymous_variant	Exon 6 of 23	2		ENSP00000409813.1		E9PC35

Frequencies

GnomAD3 genomes

AF:

0.306

AC:

46427

AN:

151702

Hom.:

7465

Cov.:

show subpopulations

Gnomad AFR

AF:

0.334

Gnomad AMI

AF:

0.398

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.275

Gnomad EAS

AF:

0.458

Gnomad SAS

AF:

0.346

Gnomad FIN

AF:

0.222

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.257

Gnomad OTH

AF:

0.296

GnomAD2 exomes

AF:

0.327

AC:

82118

AN:

251316

AF XY:

0.315

show subpopulations

Gnomad AFR exome

AF:

0.330

Gnomad AMR exome

AF:

0.546

Gnomad ASJ exome

AF:

0.258

Gnomad EAS exome

AF:

0.481

Gnomad FIN exome

AF:

0.217

Gnomad NFE exome

AF:

0.264

Gnomad OTH exome

AF:

0.302

GnomAD4 exome

AF:

0.277

AC:

402433

AN:

1451048

Hom.:

59287

Cov.:

AF XY:

0.278

AC XY:

200550

AN XY:

722626

show subpopulations

African (AFR)

AF:

0.333

AC:

11037

AN:

33186

American (AMR)

AF:

0.537

AC:

23998

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

6970

AN:

26062

East Asian (EAS)

AF:

0.433

AC:

17143

AN:

39616

South Asian (SAS)

AF:

0.328

AC:

28191

AN:

85990

European-Finnish (FIN)

AF:

0.222

AC:

11842

AN:

53416

Middle Eastern (MID)

AF:

0.225

AC:

1297

AN:

5752

European-Non Finnish (NFE)

AF:

0.258

AC:

284843

AN:

1102268

Other (OTH)

AF:

0.285

AC:

17112

AN:

60068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

13864

27728

41592

55456

69320

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9860

19720

29580

39440

49300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.306

AC:

46474

AN:

151820

Hom.:

7473

Cov.:

AF XY:

0.307

AC XY:

22771

AN XY:

74170

show subpopulations

African (AFR)

AF:

0.334

AC:

13821

AN:

41388

American (AMR)

AF:

0.446

AC:

6810

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.275

AC:

952

AN:

3466

East Asian (EAS)

AF:

0.458

AC:

2361

AN:

5160

South Asian (SAS)

AF:

0.345

AC:

1657

AN:

4798

European-Finnish (FIN)

AF:

0.222

AC:

2336

AN:

10508

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.257

AC:

17485

AN:

67930

Other (OTH)

AF:

0.297

AC:

626

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1590

3179

4769

6358

7948

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.283

Hom.:

13609

Bravo

AF:

0.325

Asia WGS

AF:

0.410

AC:

1425

AN:

3478

EpiCase

AF:

0.253

EpiControl

AF:

0.260

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.63

PhyloP100

5.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over