rs76714416

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004525.3(LRP2):c.4046-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,612,340 control chromosomes in the GnomAD database, including 761 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 353 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 408 hom. )

Consequence

LRP2
NM_004525.3 splice_region, intron

Scores

Splicing: ADA: 0.00009669

Clinical Significance

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

Conservation

PhyloP100: 1.77

Publications

4 publications found

Variant links:

COSMIC-nc: COSV55558501

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 2-169239781-A-G is Benign according to our data. Variant chr2-169239781-A-G is described in ClinVar as Benign. ClinVar VariationId is 129522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.4046-6T>C	splice_region_variant, intron_variant	Intron 25 of 78	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.4046-6T>C	splice_region_variant, intron_variant	Intron 25 of 77		XP_011509485.1
LRP2	XM_047444340.1 link	c.3122-6T>C	splice_region_variant, intron_variant	Intron 25 of 78		XP_047300296.1
LRP2	XM_011511184.3 link	c.1757-6T>C	splice_region_variant, intron_variant	Intron 10 of 63		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.4046-6T>C		splice_region_variant, intron_variant	Intron 25 of 78		NM_004525.3	ENSP00000496870.1		P98164

Frequencies

GnomAD3 genomes

AF:

0.0414

AC:

6295

AN:

152168

Hom.:

349

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.00444

Gnomad OTH

AF:

0.0444

GnomAD2 exomes

AF:

0.0167

AC:

4167

AN:

250248

AF XY:

0.0148

show subpopulations

Gnomad AFR exome

AF:

0.131

Gnomad AMR exome

AF:

0.00964

Gnomad ASJ exome

AF:

0.0362

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00580

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.00900

AC:

13146

AN:

1460054

Hom.:

408

Cov.:

AF XY:

0.00927

AC XY:

6736

AN XY:

726484

show subpopulations

African (AFR)

AF:

0.136

AC:

4556

AN:

33400

American (AMR)

AF:

0.0110

AC:

492

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0342

AC:

894

AN:

26112

East Asian (EAS)

AF:

0.000101

AC:

AN:

39672

South Asian (SAS)

AF:

0.0201

AC:

1732

AN:

86210

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.0420

AC:

242

AN:

5768

European-Non Finnish (NFE)

AF:

0.00376

AC:

4176

AN:

1110460

Other (OTH)

AF:

0.0172

AC:

1039

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

580

1159

1739

2318

2898

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.0415

AC:

6322

AN:

152286

Hom.:

353

Cov.:

AF XY:

0.0402

AC XY:

2992

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.130

AC:

5396

AN:

41548

American (AMR)

AF:

0.0188

AC:

288

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

101

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0174

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00443

AC:

301

AN:

68016

Other (OTH)

AF:

0.0440

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

286

572

857

1143

1429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0234

Hom.:

102

Bravo

AF:

0.0463

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.00894

EpiControl

AF:

0.00984

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

- -

Feb 03, 2020

GeneDx

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

- -

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

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.59

PhyloP100

1.8

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000097

dbscSNV1_RF

Benign

0.014

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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