2-169205568-G-C

Position:

• chr2-169205568-G-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.7626C>G​(p.Arg2542=) 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 (★★).

• 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

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=-0.73).
• BP6: Variant 2-169205568-G-C is Benign according to our data. Variant chr2-169205568-G-C is described in ClinVar as [Benign]. Clinvar id is 129536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169205568-G-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.7626C>G	p.Arg2542=	synonymous_variant	41/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.7626C>G	p.Arg2542=	synonymous_variant	41/78		XP_011509485.1
LRP2	XM_047444340.1	c.6702C>G	p.Arg2234=	synonymous_variant	41/79		XP_047300296.1
LRP2	XM_011511184.3	c.5337C>G	p.Arg1779=	synonymous_variant	26/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.7626C>G	p.Arg2542=	synonymous_variant	41/79		NM_004525.3	ENSP00000496870	P1

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

GnomAD3 exomes AF: 0.0688 AC: 17308 AN: 251426 Hom.: 1217 AF XY: 0.0666 AC XY: 9054 AN XY: 135880

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 SAS exome AF: 0.101

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

Gnomad4 AFR exome AF: 0.319

Gnomad4 AMR exome AF: 0.0396

Gnomad4 ASJ exome AF: 0.0237

Gnomad4 EAS exome AF: 0.00207

Gnomad4 SAS exome AF: 0.0986

Gnomad4 FIN exome AF: 0.0460

Gnomad4 NFE exome AF: 0.0557

Gnomad4 OTH exome AF: 0.0695

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

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.0689

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.00425

Gnomad4 SAS AF: 0.0997

Gnomad4 FIN AF: 0.0494

Gnomad4 NFE AF: 0.0538

Gnomad4 OTH AF: 0.0944

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

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

not specified Benign:2

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	Jul 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.6
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs13397109; hg19: chr2-170062078; COSMIC: COSV55546425;