2-169307258-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004525.3(LRP2):c.427+23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,501,660 control chromosomes in the GnomAD database, including 33,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4343 hom., cov: 32)

Exomes 𝑓: 0.20 ( 29114 hom. )

Consequence

LRP2
NM_004525.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0840

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: 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 2-169307258-T-C is Benign according to our data. Variant chr2-169307258-T-C is described in ClinVar as Benign. ClinVar VariationId is 1180910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.427+23A>G	intron_variant	Intron 4 of 78	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.427+23A>G	intron_variant	Intron 4 of 77		XP_011509485.1
LRP2	XM_047444340.1 link	c.-498+23A>G	intron_variant	Intron 4 of 78		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.427+23A>G		intron_variant	Intron 4 of 78		NM_004525.3	ENSP00000496870.1		P98164
LRP2	ENST00000443831.1 link	c.427+23A>G		intron_variant	Intron 4 of 22	2		ENSP00000409813.1		E9PC35

Frequencies

GnomAD3 genomes

AF:

0.231

AC:

35064

AN:

151896

Hom.:

4339

Cov.:

show subpopulations

Gnomad AFR

AF:

0.312

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.179

Gnomad ASJ

AF:

0.250

Gnomad EAS

AF:

0.0821

Gnomad SAS

AF:

0.193

Gnomad FIN

AF:

0.244

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.207

Gnomad OTH

AF:

0.227

GnomAD2 exomes

AF:

0.195

AC:

48877

AN:

251182

AF XY:

0.195

show subpopulations

Gnomad AFR exome

AF:

0.317

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.257

Gnomad EAS exome

AF:

0.0691

Gnomad FIN exome

AF:

0.240

Gnomad NFE exome

AF:

0.208

Gnomad OTH exome

AF:

0.203

GnomAD4 exome

AF:

0.203

AC:

274433

AN:

1349646

Hom.:

29114

Cov.:

AF XY:

0.203

AC XY:

137784

AN XY:

677922

show subpopulations

African (AFR)

AF:

0.310

AC:

9657

AN:

31142

American (AMR)

AF:

0.121

AC:

5387

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

6512

AN:

25504

East Asian (EAS)

AF:

0.118

AC:

4608

AN:

39168

South Asian (SAS)

AF:

0.191

AC:

16023

AN:

84104

European-Finnish (FIN)

AF:

0.230

AC:

12286

AN:

53336

Middle Eastern (MID)

AF:

0.236

AC:

1310

AN:

5552

European-Non Finnish (NFE)

AF:

0.205

AC:

207096

AN:

1009564

Other (OTH)

AF:

0.204

AC:

11554

AN:

56714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

10649

21297

31946

42594

53243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6826

13652

20478

27304

34130

<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:

0.231

AC:

35084

AN:

152014

Hom.:

4343

Cov.:

AF XY:

0.231

AC XY:

17159

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.312

AC:

12937

AN:

41458

American (AMR)

AF:

0.179

AC:

2728

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

867

AN:

3472

East Asian (EAS)

AF:

0.0821

AC:

425

AN:

5174

South Asian (SAS)

AF:

0.192

AC:

926

AN:

4812

European-Finnish (FIN)

AF:

0.244

AC:

2575

AN:

10550

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.207

AC:

14048

AN:

67964

Other (OTH)

AF:

0.225

AC:

473

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1338

2676

4015

5353

6691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.214

Hom.:

8694

Bravo

AF:

0.227

Asia WGS

AF:

0.131

AC:

458

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 20, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

3.8

(source)

DANN

Benign

0.56

PhyloP100

0.084

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over