rs990626

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004525.3(LRP2):​c.13113C>T​(p.Ile4371Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 1,610,642 control chromosomes in the GnomAD database, including 424,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 30943 hom., cov: 32)
Exomes 𝑓: 0.73 ( 393280 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.51
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.34).
BP6
Variant 2-169140541-G-A is Benign according to our data. Variant chr2-169140541-G-A is described in ClinVar as [Benign]. Clinvar id is 129502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169140541-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=1.51 with no splicing effect.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LRP2NM_004525.3 linkc.13113C>T p.Ile4371Ile synonymous_variant Exon 72 of 79 ENST00000649046.1 NP_004516.2 P98164Q7Z5C0Q7Z5C1
LRP2XM_011511183.4 linkc.12984C>T p.Ile4328Ile synonymous_variant Exon 71 of 78 XP_011509485.1
LRP2XM_047444340.1 linkc.12189C>T p.Ile4063Ile synonymous_variant Exon 72 of 79 XP_047300296.1
LRP2XM_011511184.3 linkc.10824C>T p.Ile3608Ile synonymous_variant Exon 57 of 64 XP_011509486.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LRP2ENST00000649046.1 linkc.13113C>T p.Ile4371Ile synonymous_variant Exon 72 of 79 NM_004525.3 ENSP00000496870.1 P98164
LRP2ENST00000649153.1 linkn.4007-931C>T intron_variant Intron 23 of 29 ENSP00000497617.1 A0A3B3IT64
LRP2ENST00000650252.1 linkn.*820-33C>T intron_variant Intron 16 of 23 ENSP00000496887.1 A0A3B3IRR0

Frequencies

GnomAD3 genomes
AF:
0.609
AC:
92431
AN:
151894
Hom.:
30938
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.316
Gnomad AMI
AF:
0.751
Gnomad AMR
AF:
0.681
Gnomad ASJ
AF:
0.633
Gnomad EAS
AF:
0.460
Gnomad SAS
AF:
0.779
Gnomad FIN
AF:
0.708
Gnomad MID
AF:
0.750
Gnomad NFE
AF:
0.749
Gnomad OTH
AF:
0.631
GnomAD3 exomes
AF:
0.691
AC:
173322
AN:
250652
Hom.:
62007
AF XY:
0.704
AC XY:
95411
AN XY:
135440
show subpopulations
Gnomad AFR exome
AF:
0.306
Gnomad AMR exome
AF:
0.736
Gnomad ASJ exome
AF:
0.652
Gnomad EAS exome
AF:
0.465
Gnomad SAS exome
AF:
0.773
Gnomad FIN exome
AF:
0.716
Gnomad NFE exome
AF:
0.746
Gnomad OTH exome
AF:
0.708
GnomAD4 exome
AF:
0.728
AC:
1062528
AN:
1458630
Hom.:
393280
Cov.:
37
AF XY:
0.731
AC XY:
530522
AN XY:
725800
show subpopulations
Gnomad4 AFR exome
AF:
0.298
Gnomad4 AMR exome
AF:
0.730
Gnomad4 ASJ exome
AF:
0.653
Gnomad4 EAS exome
AF:
0.428
Gnomad4 SAS exome
AF:
0.773
Gnomad4 FIN exome
AF:
0.715
Gnomad4 NFE exome
AF:
0.753
Gnomad4 OTH exome
AF:
0.694
GnomAD4 genome
AF:
0.608
AC:
92444
AN:
152012
Hom.:
30943
Cov.:
32
AF XY:
0.610
AC XY:
45323
AN XY:
74304
show subpopulations
Gnomad4 AFR
AF:
0.316
Gnomad4 AMR
AF:
0.681
Gnomad4 ASJ
AF:
0.633
Gnomad4 EAS
AF:
0.462
Gnomad4 SAS
AF:
0.779
Gnomad4 FIN
AF:
0.708
Gnomad4 NFE
AF:
0.749
Gnomad4 OTH
AF:
0.631
Alfa
AF:
0.718
Hom.:
69689
Bravo
AF:
0.588
Asia WGS
AF:
0.613
AC:
2130
AN:
3478
EpiCase
AF:
0.750
EpiControl
AF:
0.749

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:3
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Donnai-Barrow syndrome Benign:2
Aug 19, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.34
CADD
Benign
8.9
DANN
Benign
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.20
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.20
Position offset: -33

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: rs990626; hg19: chr2-169997051; COSMIC: COSV55577544; COSMIC: COSV55577544; API