Genetic Variant LRP2:c.79+13985G>A (chr2-169348336-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004525.3(LRP2):c.79+13985G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 151,964 control chromosomes in the GnomAD database, including 16,653 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.45 ( 16653 hom., cov: 32)

Consequence

LRP2
NM_004525.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.486

Publications

37 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.79+13985G>A		intron_variant	Intron 1 of 78	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.79+13985G>A		intron_variant	Intron 1 of 77		XP_011509485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.79+13985G>A		intron_variant	Intron 1 of 78		NM_004525.3	ENSP00000496870.1		P98164
LRP2	ENST00000443831.1 link	c.79+13985G>A		intron_variant	Intron 1 of 22	2		ENSP00000409813.1		E9PC35

Frequencies

GnomAD3 genomes

AF:

0.446

AC:

67665

AN:

151846

Hom.:

16608

Cov.:

show subpopulations

Gnomad AFR

AF:

0.664

Gnomad AMI

AF:

0.300

Gnomad AMR

AF:

0.332

Gnomad ASJ

AF:

0.447

Gnomad EAS

AF:

0.471

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.297

Gnomad MID

AF:

0.402

Gnomad NFE

AF:

0.372

Gnomad OTH

AF:

0.442

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.446

AC:

67756

AN:

151964

Hom.:

16653

Cov.:

AF XY:

0.442

AC XY:

32830

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.664

AC:

27531

AN:

41438

American (AMR)

AF:

0.331

AC:

5049

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.447

AC:

1551

AN:

3470

East Asian (EAS)

AF:

0.471

AC:

2426

AN:

5148

South Asian (SAS)

AF:

0.298

AC:

1437

AN:

4820

European-Finnish (FIN)

AF:

0.297

AC:

3133

AN:

10558

Middle Eastern (MID)

AF:

0.395

AC:

116

AN:

294

European-Non Finnish (NFE)

AF:

0.372

AC:

25309

AN:

67954

Other (OTH)

AF:

0.440

AC:

931

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1761

3522

5283

7044

8805

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

598

1196

1794

2392

2990

<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:

0.404

Hom.:

9786

Bravo

AF:

0.460

Asia WGS

AF:

0.395

AC:

1375

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.7

(source)

DANN

Benign

0.52

PhyloP100

-0.49

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over