rs587776717

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_004525.3(LRP2):​c.2640-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

LRP2
NM_004525.3 splice_acceptor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 7.45
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3, offset of 23, new splice context is: ttcacgattgtactgggtAGatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-169256237-C-T is Pathogenic according to our data. Variant chr2-169256237-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9452.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LRP2NM_004525.3 linkuse as main transcriptc.2640-1G>A splice_acceptor_variant, intron_variant ENST00000649046.1 NP_004516.2 P98164Q7Z5C0Q7Z5C1
LRP2XM_011511183.4 linkuse as main transcriptc.2640-1G>A splice_acceptor_variant, intron_variant XP_011509485.1
LRP2XM_047444340.1 linkuse as main transcriptc.1716-1G>A splice_acceptor_variant, intron_variant XP_047300296.1
LRP2XM_011511184.3 linkuse as main transcriptc.351-1G>A splice_acceptor_variant, intron_variant XP_011509486.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LRP2ENST00000649046.1 linkuse as main transcriptc.2640-1G>A splice_acceptor_variant, intron_variant NM_004525.3 ENSP00000496870.1 P98164
LRP2ENST00000443831.1 linkuse as main transcriptc.2229-1G>A splice_acceptor_variant, intron_variant 2 ENSP00000409813.1 E9PC35

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Donnai-Barrow syndrome Pathogenic:2Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 01, 2007- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 08, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.68
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
33
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
1.0
D
GERP RS
5.5

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.33
Position offset: -24
DS_AL_spliceai
0.98
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587776717; hg19: chr2-170112747; API