2-169289151-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_004525.3(LRP2):c.923-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00949 in 1,613,810 control chromosomes in the GnomAD database, including 198 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0073 ( 15 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 183 hom. )

Consequence

LRP2
NM_004525.3 splice_region, intron

Scores

Splicing: ADA: 0.00004351

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.0380

Publications

6 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 2-169289151-C-T is Benign according to our data. Variant chr2-169289151-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129545.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
LRP2	NM_004525.3 link	c.923-6G>A	splice_region_variant, intron_variant	Intron 8 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4 link	c.923-6G>A	splice_region_variant, intron_variant	Intron 8 of 77		XP_011509485.1
LRP2	XM_047444340.1 link	c.-2-6G>A	splice_region_variant, intron_variant	Intron 8 of 78		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.923-6G>A		splice_region_variant, intron_variant	Intron 8 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1 link	c.923-6G>A		splice_region_variant, intron_variant	Intron 8 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes

AF:

0.00736

AC:

1119

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00765

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0368

Gnomad FIN

AF:

0.00302

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.00853

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.0114

AC:

2852

AN:

251208

AF XY:

0.0133

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00758

Gnomad ASJ exome

AF:

0.0270

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00208

Gnomad NFE exome

AF:

0.00810

Gnomad OTH exome

AF:

0.0150

GnomAD4 exome

AF:

0.00972

AC:

14202

AN:

1461608

Hom.:

183

Cov.:

AF XY:

0.0109

AC XY:

7943

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

33470

American (AMR)

AF:

0.00783

AC:

350

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0287

AC:

749

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.0401

AC:

3462

AN:

86258

European-Finnish (FIN)

AF:

0.00219

AC:

117

AN:

53378

Middle Eastern (MID)

AF:

0.0572

AC:

330

AN:

5766

European-Non Finnish (NFE)

AF:

0.00757

AC:

8413

AN:

1111826

Other (OTH)

AF:

0.0120

AC:

726

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

774

1548

2322

3096

3870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

364

728

1092

1456

1820

<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:

0.00730

AC:

1111

AN:

152202

Hom.:

Cov.:

AF XY:

0.00799

AC XY:

595

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

41524

American (AMR)

AF:

0.00764

AC:

117

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0311

AC:

108

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.0360

AC:

173

AN:

4812

European-Finnish (FIN)

AF:

0.00302

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00853

AC:

580

AN:

67992

Other (OTH)

AF:

0.00994

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

125

187

250

312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00812

Hom.:

Bravo

AF:

0.00658

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0120

EpiControl

AF:

0.0116

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 18, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Donnai-Barrow syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely 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

-0.50

CADD

Benign

2.4

(source)

DANN

Benign

0.46

PhyloP100

-0.038

Mutation Taster

=86/14

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000044

dbscSNV1_RF

Benign

0.0080

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over