chr2-169205568-G-C

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.7626C>G(p.Arg2542Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0677 in 1,613,650 control chromosomes in the GnomAD database, including 6,434 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. R2542R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 2161 hom., cov: 32)

Exomes 𝑓: 0.062 ( 4273 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.288

Publications

13 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
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

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=-0.73).

BP6

Variant 2-169205568-G-C is Benign according to our data. Variant chr2-169205568-G-C is described in ClinVar as Benign. ClinVar VariationId is 129536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.288 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 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.7626C>G	p.Arg2542Arg	synonymous	Exon 41 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.7626C>G	p.Arg2542Arg	synonymous	Exon 41 of 79	ENSP00000496870.1	P98164

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18804

AN:

151834

Hom.:

2156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.307

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0691

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.100

Gnomad FIN

AF:

0.0494

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0538

Gnomad OTH

AF:

0.0954

GnomAD2 exomes

AF:

0.0688

AC:

17308

AN:

251426

AF XY:

0.0666

show subpopulations

Gnomad AFR exome

AF:

0.313

Gnomad AMR exome

AF:

0.0351

Gnomad ASJ exome

AF:

0.0271

Gnomad EAS exome

AF:

0.00392

Gnomad FIN exome

AF:

0.0475

Gnomad NFE exome

AF:

0.0541

Gnomad OTH exome

AF:

0.0618

GnomAD4 exome

AF:

0.0619

AC:

90493

AN:

1461698

Hom.:

4273

Cov.:

AF XY:

0.0623

AC XY:

45281

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.319

AC:

10687

AN:

33468

American (AMR)

AF:

0.0396

AC:

1769

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0237

AC:

620

AN:

26136

East Asian (EAS)

AF:

0.00207

AC:

AN:

39694

South Asian (SAS)

AF:

0.0986

AC:

8505

AN:

86254

European-Finnish (FIN)

AF:

0.0460

AC:

2458

AN:

53420

Middle Eastern (MID)

AF:

0.0518

AC:

299

AN:

5768

European-Non Finnish (NFE)

AF:

0.0557

AC:

61876

AN:

1111848

Other (OTH)

AF:

0.0695

AC:

4197

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

4585

9169

13754

18338

22923

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2466

4932

7398

9864

12330

<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:

0.124

AC:

18830

AN:

151952

Hom.:

2161

Cov.:

AF XY:

0.122

AC XY:

9061

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.307

AC:

12719

AN:

41384

American (AMR)

AF:

0.0689

AC:

1052

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

AN:

3470

East Asian (EAS)

AF:

0.00425

AC:

AN:

5172

South Asian (SAS)

AF:

0.0997

AC:

480

AN:

4816

European-Finnish (FIN)

AF:

0.0494

AC:

521

AN:

10556

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0538

AC:

3655

AN:

67976

Other (OTH)

AF:

0.0944

AC:

199

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

751

1503

2254

3006

3757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

384

576

768

960

<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:

0.0424

Hom.:

Bravo

AF:

0.133

Asia WGS

AF:

0.0710

AC:

247

AN:

3478

EpiCase

AF:

0.0539

EpiControl

AF:

0.0538

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Donnai-Barrow syndrome (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.6

(source)

DANN

Benign

0.67

PhyloP100

0.29

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over