2-169259078-T-C

Position:

• chr2-169259078-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004525.3(LRP2):​c.2460A>G​(p.Thr820Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 1,612,380 control chromosomes in the GnomAD database, including 206,412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23672 hom., cov: 30)
  • Exomes 𝑓: 0.49 (182740 hom.)
• Consequence: LRP2 NM_004525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.419

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-169259078-T-C is Benign according to our data. Variant chr2-169259078-T-C is described in ClinVar as [Benign]. Clinvar id is 129510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169259078-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.419 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.2460A>G	p.Thr820Thr	synonymous_variant	17/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.2460A>G	p.Thr820Thr	synonymous_variant	17/78		XP_011509485.1
LRP2	XM_047444340.1	c.1536A>G	p.Thr512Thr	synonymous_variant	17/79		XP_047300296.1
LRP2	XM_011511184.3	c.171A>G	p.Thr57Thr	synonymous_variant	2/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.2460A>G	p.Thr820Thr	synonymous_variant	17/79		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.2049A>G	p.Thr683Thr	synonymous_variant	15/23	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83113 AN: 151526 Hom.: 23636 Cov.: 30

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.478

Gnomad SAS AF: 0.755

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.550

GnomAD3 exomes AF: 0.546 AC: 137151 AN: 251078 Hom.: 39517 AF XY: 0.548 AC XY: 74361 AN XY: 135690

Gnomad AFR exome AF: 0.694

Gnomad AMR exome AF: 0.686

Gnomad ASJ exome AF: 0.543

Gnomad EAS exome AF: 0.476

Gnomad SAS exome AF: 0.753

Gnomad FIN exome AF: 0.391

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.492 AC: 718665 AN: 1460736 Hom.: 182740 Cov.: 44 AF XY: 0.499 AC XY: 362906 AN XY: 726712

Gnomad4 AFR exome AF: 0.691

Gnomad4 AMR exome AF: 0.677

Gnomad4 ASJ exome AF: 0.526

Gnomad4 EAS exome AF: 0.458

Gnomad4 SAS exome AF: 0.747

Gnomad4 FIN exome AF: 0.394

Gnomad4 NFE exome AF: 0.463

Gnomad4 OTH exome AF: 0.512

GnomAD4 genome AF: 0.549 AC: 83203 AN: 151644 Hom.: 23672 Cov.: 30 AF XY: 0.550 AC XY: 40714 AN XY: 74086

Gnomad4 AFR AF: 0.687

Gnomad4 AMR AF: 0.608

Gnomad4 ASJ AF: 0.512

Gnomad4 EAS AF: 0.478

Gnomad4 SAS AF: 0.752

Gnomad4 FIN AF: 0.387

Gnomad4 NFE AF: 0.470

Gnomad4 OTH AF: 0.555

Alfa AF: 0.496 Hom.: 31146

Bravo AF: 0.567

Asia WGS AF: 0.650 AC: 2260 AN: 3478

EpiCase AF: 0.479

EpiControl AF: 0.481

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Donnai-Barrow syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1
DANN	Benign	0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2241190; hg19: chr2-170115588; COSMIC: COSV55546459;