chr2-169307306-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004525.3(LRP2):c.402C>A(p.Pro134Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 1,612,032 control chromosomes in the GnomAD database, including 4,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P134P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.070 ( 427 hom., cov: 32)

Exomes 𝑓: 0.072 ( 4193 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.63

Publications

9 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 2-169307306-G-T is Benign according to our data. Variant chr2-169307306-G-T is described in CliVar as Benign. Clinvar id is 129521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169307306-G-T is described in CliVar as Benign. Clinvar id is 129521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169307306-G-T is described in CliVar as Benign. Clinvar id is 129521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.63 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.078 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.402C>A	p.Pro134Pro	synonymous_variant	Exon 4 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.402C>A	p.Pro134Pro	synonymous_variant	Exon 4 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.-523C>A		5_prime_UTR_variant	Exon 4 of 79		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.402C>A	p.Pro134Pro	synonymous_variant	Exon 4 of 79		NM_004525.3	ENSP00000496870.1		P98164
LRP2	ENST00000443831.1 link	c.402C>A	p.Pro134Pro	synonymous_variant	Exon 4 of 23	2		ENSP00000409813.1		E9PC35

Frequencies

GnomAD3 genomes

AF:

0.0699

AC:

10637

AN:

152100

Hom.:

425

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0619

Gnomad AMI

AF:

0.228

Gnomad AMR

AF:

0.0752

Gnomad ASJ

AF:

0.0565

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0369

Gnomad FIN

AF:

0.0693

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0798

Gnomad OTH

AF:

0.0731

GnomAD2 exomes

AF:

0.0603

AC:

15137

AN:

251234

AF XY:

0.0613

show subpopulations

Gnomad AFR exome

AF:

0.0649

Gnomad AMR exome

AF:

0.0480

Gnomad ASJ exome

AF:

0.0502

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0655

Gnomad NFE exome

AF:

0.0800

Gnomad OTH exome

AF:

0.0635

GnomAD4 exome

AF:

0.0720

AC:

105079

AN:

1459814

Hom.:

4193

Cov.:

AF XY:

0.0712

AC XY:

51697

AN XY:

726308

show subpopulations

African (AFR)

AF:

0.0612

AC:

2045

AN:

33442

American (AMR)

AF:

0.0491

AC:

2197

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0509

AC:

1329

AN:

26124

East Asian (EAS)

AF:

0.000176

AC:

AN:

39686

South Asian (SAS)

AF:

0.0336

AC:

2898

AN:

86244

European-Finnish (FIN)

AF:

0.0644

AC:

3437

AN:

53404

Middle Eastern (MID)

AF:

0.0649

AC:

374

AN:

5764

European-Non Finnish (NFE)

AF:

0.0799

AC:

88736

AN:

1110100

Other (OTH)

AF:

0.0672

AC:

4056

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

4343

8687

13030

17374

21717

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3198

6396

9594

12792

15990

<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:

0.0699

AC:

10645

AN:

152218

Hom.:

427

Cov.:

AF XY:

0.0696

AC XY:

5181

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0620

AC:

2576

AN:

41532

American (AMR)

AF:

0.0751

AC:

1148

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0565

AC:

196

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0367

AC:

177

AN:

4824

European-Finnish (FIN)

AF:

0.0693

AC:

734

AN:

10598

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0798

AC:

5424

AN:

68004

Other (OTH)

AF:

0.0724

AC:

153

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

505

1010

1514

2019

2524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0660

Hom.:

266

Bravo

AF:

0.0703

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0840

EpiControl

AF:

0.0888

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

- -

Feb 21, 2019

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

Jan 12, 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. -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.056

(source)

DANN

Benign

0.42

PhyloP100

-3.6

Mutation Taster

=92/8

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