rs2302694

Positions:

• chr2-169231841-G-A

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.5100C>T​(p.Ser1700=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,613,526 control chromosomes in the GnomAD database, including 14,569 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3804 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10765 hom.)
• Consequence: LRP2 NM_004525.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001138
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.145

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=-0.81).
• BP6: Variant 2-169231841-G-A is Benign according to our data. Variant chr2-169231841-G-A is described in ClinVar as [Benign]. Clinvar id is 129528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169231841-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.145 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.5100C>T	p.Ser1700=	splice_region_variant, synonymous_variant	31/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.5100C>T	p.Ser1700=	splice_region_variant, synonymous_variant	31/78		XP_011509485.1
LRP2	XM_047444340.1	c.4176C>T	p.Ser1392=	splice_region_variant, synonymous_variant	31/79		XP_047300296.1
LRP2	XM_011511184.3	c.2811C>T	p.Ser937=	splice_region_variant, synonymous_variant	16/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.5100C>T	p.Ser1700=	splice_region_variant, synonymous_variant	31/79		NM_004525.3	ENSP00000496870	P1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27962 AN: 151954 Hom.: 3801 Cov.: 32

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0548

Gnomad SAS AF: 0.0766

Gnomad FIN AF: 0.0417

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.122 AC: 30634 AN: 250754 Hom.: 2688 AF XY: 0.115 AC XY: 15603 AN XY: 135554

Gnomad AFR exome AF: 0.389

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.0479

Gnomad SAS exome AF: 0.0880

Gnomad FIN exome AF: 0.0447

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.111 AC: 161574 AN: 1461454 Hom.: 10765 Cov.: 33 AF XY: 0.109 AC XY: 79418 AN XY: 727024

Gnomad4 AFR exome AF: 0.395

Gnomad4 AMR exome AF: 0.166

Gnomad4 ASJ exome AF: 0.162

Gnomad4 EAS exome AF: 0.0788

Gnomad4 SAS exome AF: 0.0890

Gnomad4 FIN exome AF: 0.0469

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.184 AC: 28003 AN: 152072 Hom.: 3804 Cov.: 32 AF XY: 0.178 AC XY: 13247 AN XY: 74348

Gnomad4 AFR AF: 0.383

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.0550

Gnomad4 SAS AF: 0.0763

Gnomad4 FIN AF: 0.0417

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.184

Alfa AF: 0.120 Hom.: 3416

Bravo AF: 0.205

Asia WGS AF: 0.112 AC: 391 AN: 3478

EpiCase AF: 0.109

EpiControl AF: 0.110

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	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

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

Donnai-Barrow syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.38
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0
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: rs2302694; hg19: chr2-170088351; COSMIC: COSV55553497;