2-169205568-G-C

Variant names:

• chr2-169205568-G-C
• rs13397109
• NM_004525.3:c.7626C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004525.3(LRP2):​c.7626C>G​(p.Arg2542Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0677 in 1,613,650 control chromosomes in the GnomAD database, including 6,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R2542R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (2161 hom., cov: 32)
  • Exomes 𝑓: 0.062 (4273 hom.)
• Consequence: LRP2 NM_004525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.288
• Publications: 13 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-169205568-G-C is Benign according to our data. Variant chr2-169205568-G-C is described in ClinVar as Benign. ClinVar VariationId is 129536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.288 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.7626C>G	p.Arg2542Arg	synonymous	Exon 41 of 79	NP_004516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.7626C>G	p.Arg2542Arg	synonymous	Exon 41 of 79	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18804 AN: 151834 Hom.: 2156 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0691

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0494

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0538

Gnomad OTH AF: 0.0954

GnomAD2 exomes AF: 0.0688 AC: 17308 AN: 251426 AF XY: 0.0666

Gnomad AFR exome AF: 0.313

Gnomad AMR exome AF: 0.0351

Gnomad ASJ exome AF: 0.0271

Gnomad EAS exome AF: 0.00392

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.0541

Gnomad OTH exome AF: 0.0618

GnomAD4 exome AF: 0.0619 AC: 90493 AN: 1461698 Hom.: 4273 Cov.: 33 AF XY: 0.0623 AC XY: 45281 AN XY: 727168

African (AFR) AF: 0.319 AC: 10687 AN: 33468

American (AMR) AF: 0.0396 AC: 1769 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 620 AN: 26136

East Asian (EAS) AF: 0.00207 AC: 82 AN: 39694

South Asian (SAS) AF: 0.0986 AC: 8505 AN: 86254

European-Finnish (FIN) AF: 0.0460 AC: 2458 AN: 53420

Middle Eastern (MID) AF: 0.0518 AC: 299 AN: 5768

European-Non Finnish (NFE) AF: 0.0557 AC: 61876 AN: 1111848

Other (OTH) AF: 0.0695 AC: 4197 AN: 60388

GnomAD4 genome AF: 0.124 AC: 18830 AN: 151952 Hom.: 2161 Cov.: 32 AF XY: 0.122 AC XY: 9061 AN XY: 74286

African (AFR) AF: 0.307 AC: 12719 AN: 41384

American (AMR) AF: 0.0689 AC: 1052 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3470

East Asian (EAS) AF: 0.00425 AC: 22 AN: 5172

South Asian (SAS) AF: 0.0997 AC: 480 AN: 4816

European-Finnish (FIN) AF: 0.0494 AC: 521 AN: 10556

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0538 AC: 3655 AN: 67976

Other (OTH) AF: 0.0944 AC: 199 AN: 2108

Alfa AF: 0.0424 Hom.: 88

Bravo AF: 0.133

Asia WGS AF: 0.0710 AC: 247 AN: 3478

EpiCase AF: 0.0539

EpiControl AF: 0.0538

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Donnai-Barrow syndrome Benign:2

Jan 12, 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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.6
DANN	Benign	0.67
PhyloP100		0.29
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs13397109; hg19: chr2-170062078;