chr2-169242963-T-C

Variant names:

• chr2-169242963-T-C
• rs831042
• NM_004525.3:c.3660A>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.3660A>G​(p.Ala1220Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 1,609,298 control chromosomes in the GnomAD database, including 189,124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20371 hom., cov: 32)
  • Exomes 𝑓: 0.47 (168753 hom.)
• Consequence: LRP2 NM_004525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.757
• Publications: 25 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=-0.74).
• BP6: Variant 2-169242963-T-C is Benign according to our data. Variant chr2-169242963-T-C is described in ClinVar as Benign. ClinVar VariationId is 129519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.757 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.711 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.3660A>G	p.Ala1220Ala	synonymous	Exon 24 of 79	NP_004516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.3660A>G	p.Ala1220Ala	synonymous	Exon 24 of 79	ENSP00000496870.1
	LRP2	ENST00000443831.1	TSL:2	c.3249A>G	p.Ala1083Ala	synonymous	Exon 22 of 23	ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77686 AN: 151912 Hom.: 20339 Cov.: 32

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.734

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.511

GnomAD2 exomes AF: 0.524 AC: 131842 AN: 251448 AF XY: 0.527

Gnomad AFR exome AF: 0.606

Gnomad AMR exome AF: 0.666

Gnomad ASJ exome AF: 0.506

Gnomad EAS exome AF: 0.475

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.453

Gnomad OTH exome AF: 0.484

GnomAD4 exome AF: 0.473 AC: 689805 AN: 1457268 Hom.: 168753 Cov.: 33 AF XY: 0.480 AC XY: 348457 AN XY: 725222

African (AFR) AF: 0.599 AC: 19982 AN: 33334

American (AMR) AF: 0.656 AC: 29312 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 12770 AN: 26080

East Asian (EAS) AF: 0.456 AC: 18111 AN: 39678

South Asian (SAS) AF: 0.722 AC: 62220 AN: 86178

European-Finnish (FIN) AF: 0.387 AC: 20687 AN: 53404

Middle Eastern (MID) AF: 0.507 AC: 2916 AN: 5756

European-Non Finnish (NFE) AF: 0.446 AC: 494505 AN: 1107880

Other (OTH) AF: 0.486 AC: 29302 AN: 60246

GnomAD4 genome AF: 0.512 AC: 77770 AN: 152030 Hom.: 20371 Cov.: 32 AF XY: 0.514 AC XY: 38177 AN XY: 74296

African (AFR) AF: 0.598 AC: 24813 AN: 41476

American (AMR) AF: 0.582 AC: 8889 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 1669 AN: 3468

East Asian (EAS) AF: 0.476 AC: 2455 AN: 5158

South Asian (SAS) AF: 0.731 AC: 3525 AN: 4820

European-Finnish (FIN) AF: 0.383 AC: 4038 AN: 10556

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30775 AN: 67966

Other (OTH) AF: 0.517 AC: 1090 AN: 2110

Alfa AF: 0.481 Hom.: 28694

Bravo AF: 0.527

Asia WGS AF: 0.637 AC: 2216 AN: 3478

EpiCase AF: 0.459

EpiControl AF: 0.460

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

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.

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.7
DANN	Benign	0.48
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs831042; hg19: chr2-170099473; COSMIC: COSV55546437;