chr2-169294161-G-A

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:8

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: G2P, Labcorp Genetics (formerly Invitae), Orphanet
Stickler syndrome
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: G2P
congenital heart disease
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

LRP2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_004525.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.639C>T	p.Asp213Asp	synonymous	Exon 6 of 79	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.639C>T	p.Asp213Asp	synonymous	Exon 6 of 79	ENSP00000496870.1	P98164
	LRP2	ENST00000443831.1	TSL:2	c.639C>T	p.Asp213Asp	synonymous	Exon 6 of 23	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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Donnai-Barrow syndrome (2)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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