chr2-169246826-T-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.3069A>G(p.Thr1023Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,613,722 control chromosomes in the GnomAD database, including 198,654 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 23270 hom., cov: 32)

Exomes 𝑓: 0.48 ( 175384 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.936

Publications

27 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=-0.85).

BP6

Variant 2-169246826-T-C is Benign according to our data. Variant chr2-169246826-T-C is described in ClinVar as Benign. ClinVar VariationId is 129516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.936 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.727 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.3069A>G	p.Thr1023Thr	synonymous	Exon 21 of 79	NP_004516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.3069A>G	p.Thr1023Thr	synonymous	Exon 21 of 79	ENSP00000496870.1
	LRP2	ENST00000443831.1	TSL:2	c.2658A>G	p.Thr886Thr	synonymous	Exon 19 of 23	ENSP00000409813.1

Frequencies

GnomAD3 genomes

AF:

0.542

AC:

82313

AN:

151868

Hom.:

23236

Cov.:

show subpopulations

Gnomad AFR

AF:

0.690

Gnomad AMI

AF:

0.438

Gnomad AMR

AF:

0.597

Gnomad ASJ

AF:

0.511

Gnomad EAS

AF:

0.477

Gnomad SAS

AF:

0.750

Gnomad FIN

AF:

0.383

Gnomad MID

AF:

0.592

Gnomad NFE

AF:

0.457

Gnomad OTH

AF:

0.540

GnomAD2 exomes

AF:

0.538

AC:

135235

AN:

251424

AF XY:

0.540

show subpopulations

Gnomad AFR exome

AF:

0.697

Gnomad AMR exome

AF:

0.673

Gnomad ASJ exome

AF:

0.542

Gnomad EAS exome

AF:

0.476

Gnomad FIN exome

AF:

0.386

Gnomad NFE exome

AF:

0.458

Gnomad OTH exome

AF:

0.497

GnomAD4 exome

AF:

0.481

AC:

703444

AN:

1461736

Hom.:

175384

Cov.:

AF XY:

0.489

AC XY:

355339

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.695

AC:

23255

AN:

33476

American (AMR)

AF:

0.663

AC:

29667

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.524

AC:

13697

AN:

26136

East Asian (EAS)

AF:

0.457

AC:

18135

AN:

39700

South Asian (SAS)

AF:

0.741

AC:

63896

AN:

86254

European-Finnish (FIN)

AF:

0.388

AC:

20713

AN:

53418

Middle Eastern (MID)

AF:

0.542

AC:

3128

AN:

5768

European-Non Finnish (NFE)

AF:

0.450

AC:

500695

AN:

1111868

Other (OTH)

AF:

0.501

AC:

30258

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

20514

41028

61542

82056

102570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15230

30460

45690

60920

76150

<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:

0.542

AC:

82403

AN:

151986

Hom.:

23270

Cov.:

AF XY:

0.544

AC XY:

40376

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.690

AC:

28627

AN:

41460

American (AMR)

AF:

0.597

AC:

9128

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.511

AC:

1773

AN:

3472

East Asian (EAS)

AF:

0.477

AC:

2453

AN:

5144

South Asian (SAS)

AF:

0.748

AC:

3600

AN:

4816

European-Finnish (FIN)

AF:

0.383

AC:

4046

AN:

10568

Middle Eastern (MID)

AF:

0.592

AC:

173

AN:

292

European-Non Finnish (NFE)

AF:

0.457

AC:

31055

AN:

67932

Other (OTH)

AF:

0.545

AC:

1149

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1846

3692

5539

7385

9231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

708

1416

2124

2832

3540

<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:

0.492

Hom.:

55855

Bravo

AF:

0.560

Asia WGS

AF:

0.650

AC:

2259

AN:

3478

EpiCase

AF:

0.468

EpiControl

AF:

0.469

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

-0.85

CADD

Benign

0.36

(source)

DANN

Benign

0.28

PhyloP100

-0.94

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

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over