chr2-169235885-A-G

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.4875T>C(p.Cys1625Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,613,596 control chromosomes in the GnomAD database, including 71,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 13586 hom., cov: 32)

Exomes 𝑓: 0.26 ( 57516 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.75

Publications

24 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=-0.48).

BP6

Variant 2-169235885-A-G is Benign according to our data. Variant chr2-169235885-A-G is described in ClinVar as Benign. ClinVar VariationId is 129526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.75 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.4875T>C	p.Cys1625Cys	synonymous	Exon 29 of 79	NP_004516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.4875T>C	p.Cys1625Cys	synonymous	Exon 29 of 79	ENSP00000496870.1

Frequencies

GnomAD3 genomes

AF:

0.383

AC:

58261

AN:

151994

Hom.:

13564

Cov.:

show subpopulations

Gnomad AFR

AF:

0.651

Gnomad AMI

AF:

0.226

Gnomad AMR

AF:

0.437

Gnomad ASJ

AF:

0.348

Gnomad EAS

AF:

0.411

Gnomad SAS

AF:

0.369

Gnomad FIN

AF:

0.190

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.241

Gnomad OTH

AF:

0.391

GnomAD2 exomes

AF:

0.334

AC:

84008

AN:

251412

AF XY:

0.324

show subpopulations

Gnomad AFR exome

AF:

0.660

Gnomad AMR exome

AF:

0.486

Gnomad ASJ exome

AF:

0.381

Gnomad EAS exome

AF:

0.418

Gnomad FIN exome

AF:

0.198

Gnomad NFE exome

AF:

0.241

Gnomad OTH exome

AF:

0.314

GnomAD4 exome

AF:

0.264

AC:

385576

AN:

1461484

Hom.:

57516

Cov.:

AF XY:

0.266

AC XY:

193589

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.663

AC:

22203

AN:

33474

American (AMR)

AF:

0.485

AC:

21692

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.363

AC:

9480

AN:

26132

East Asian (EAS)

AF:

0.390

AC:

15502

AN:

39698

South Asian (SAS)

AF:

0.363

AC:

31273

AN:

86244

European-Finnish (FIN)

AF:

0.202

AC:

10808

AN:

53406

Middle Eastern (MID)

AF:

0.368

AC:

2122

AN:

5766

European-Non Finnish (NFE)

AF:

0.229

AC:

254554

AN:

1111658

Other (OTH)

AF:

0.297

AC:

17942

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

14888

29776

44665

59553

74441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8992

17984

26976

35968

44960

<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:

0.384

AC:

58336

AN:

152112

Hom.:

13586

Cov.:

AF XY:

0.381

AC XY:

28308

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.651

AC:

27016

AN:

41484

American (AMR)

AF:

0.437

AC:

6670

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.348

AC:

1209

AN:

3472

East Asian (EAS)

AF:

0.412

AC:

2127

AN:

5166

South Asian (SAS)

AF:

0.367

AC:

1768

AN:

4816

European-Finnish (FIN)

AF:

0.190

AC:

2011

AN:

10594

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.241

AC:

16393

AN:

67984

Other (OTH)

AF:

0.390

AC:

824

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1611

3222

4833

6444

8055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.311

Hom.:

10165

Bravo

AF:

0.416

Asia WGS

AF:

0.402

AC:

1400

AN:

3478

EpiCase

AF:

0.252

EpiControl

AF:

0.258

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Donnai-Barrow syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.9

(source)

DANN

Benign

0.63

PhyloP100

1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over