NM_004525.3:c.13113C>T

Variant names:

• chr2-169140541-G-A
• rs990626
• NM_004525.3:c.13113C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.51

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]

ACMG classification

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
LRP2	NM_004525.3	c.13113C>T	p.Ile4371Ile	synonymous_variant	Exon 72 of 79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.12984C>T	p.Ile4328Ile	synonymous_variant	Exon 71 of 78		XP_011509485.1
LRP2	XM_047444340.1	c.12189C>T	p.Ile4063Ile	synonymous_variant	Exon 72 of 79		XP_047300296.1
LRP2	XM_011511184.3	c.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
LRP2	ENST00000649046.1	c.13113C>T	p.Ile4371Ile	synonymous_variant	Exon 72 of 79		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000649153.1	n.4007-931C>T		intron_variant	Intron 23 of 29			ENSP00000497617.1
LRP2	ENST00000650252.1	n.*820-33C>T		intron_variant	Intron 16 of 23			ENSP00000496887.1

Frequencies

GnomAD3 genomes AF: 0.609 AC: 92431 AN: 151894 Hom.: 30938 Cov.: 32

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

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

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

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

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

Other links and lift over

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