rs2302694

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.5100C>T(p.Ser1700Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,613,526 control chromosomes in the GnomAD database, including 14,569 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1700S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.18 ( 3804 hom., cov: 32)

Exomes 𝑓: 0.11 ( 10765 hom. )

Consequence

LRP2
NM_004525.3 splice_region, synonymous

Scores

Splicing: ADA: 0.00001138

Clinical Significance

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

Conservation

PhyloP100: 0.145

Publications

23 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=-0.81).

BP6

Variant 2-169231841-G-A is Benign according to our data. Variant chr2-169231841-G-A is described in ClinVar as Benign. ClinVar VariationId is 129528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.145 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.378 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.5100C>T	p.Ser1700Ser	splice_region synonymous	Exon 31 of 79	NP_004516.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.5100C>T	p.Ser1700Ser	splice_region synonymous	Exon 31 of 79	ENSP00000496870.1

Frequencies

GnomAD3 genomes

AF:

0.184

AC:

27962

AN:

151954

Hom.:

3801

Cov.:

show subpopulations

Gnomad AFR

AF:

0.383

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.188

Gnomad ASJ

AF:

0.156

Gnomad EAS

AF:

0.0548

Gnomad SAS

AF:

0.0766

Gnomad FIN

AF:

0.0417

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.186

GnomAD2 exomes

AF:

0.122

AC:

30634

AN:

250754

AF XY:

0.115

show subpopulations

Gnomad AFR exome

AF:

0.389

Gnomad AMR exome

AF:

0.163

Gnomad ASJ exome

AF:

0.171

Gnomad EAS exome

AF:

0.0479

Gnomad FIN exome

AF:

0.0447

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.126

GnomAD4 exome

AF:

0.111

AC:

161574

AN:

1461454

Hom.:

10765

Cov.:

AF XY:

0.109

AC XY:

79418

AN XY:

727024

show subpopulations

African (AFR)

AF:

0.395

AC:

13220

AN:

33452

American (AMR)

AF:

0.166

AC:

7410

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.162

AC:

4244

AN:

26124

East Asian (EAS)

AF:

0.0788

AC:

3128

AN:

39688

South Asian (SAS)

AF:

0.0890

AC:

7679

AN:

86254

European-Finnish (FIN)

AF:

0.0469

AC:

2503

AN:

53400

Middle Eastern (MID)

AF:

0.155

AC:

893

AN:

5754

European-Non Finnish (NFE)

AF:

0.103

AC:

114799

AN:

1111732

Other (OTH)

AF:

0.128

AC:

7698

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

7747

15494

23240

30987

38734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4410

8820

13230

17640

22050

<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:

0.184

AC:

28003

AN:

152072

Hom.:

3804

Cov.:

AF XY:

0.178

AC XY:

13247

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.383

AC:

15859

AN:

41420

American (AMR)

AF:

0.188

AC:

2877

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.156

AC:

540

AN:

3466

East Asian (EAS)

AF:

0.0550

AC:

284

AN:

5168

South Asian (SAS)

AF:

0.0763

AC:

367

AN:

4812

European-Finnish (FIN)

AF:

0.0417

AC:

442

AN:

10598

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.104

AC:

7089

AN:

68010

Other (OTH)

AF:

0.184

AC:

389

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1048

2096

3145

4193

5241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

268

536

804

1072

1340

<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:

0.127

Hom.:

5413

Bravo

AF:

0.205

Asia WGS

AF:

0.112

AC:

391

AN:

3478

EpiCase

AF:

0.109

EpiControl

AF:

0.110

ClinVar

ClinVar submissions as Germline

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

-0.81

CADD

Benign

0.38

(source)

DANN

Benign

0.40

PhyloP100

0.14

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000011

dbscSNV1_RF

Benign

0.0

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

Computational scores

Splicing

Publications

Other links and lift over