rs2302694

Variant names:

• chr2-169231841-G-A
• rs2302694
• NM_004525.3:c.5100C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-169231841-G-A
• chr2-169231841-G-C

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.5100C>T​(p.Ser1700Ser) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S1700S) has been classified as Likely 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
• Publications: 23 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=-0.81).
• BP6: Variant 2-169231841-G-A is Benign according to our data. Variant chr2-169231841-G-A is described in ClinVar as Benign. ClinVar VariationId is 129528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.5100C>T	p.Ser1700Ser	splice_region_variant, synonymous_variant	Exon 31 of 79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.5100C>T	p.Ser1700Ser	splice_region_variant, synonymous_variant	Exon 31 of 78		XP_011509485.1
LRP2	XM_047444340.1	c.4176C>T	p.Ser1392Ser	splice_region_variant, synonymous_variant	Exon 31 of 79		XP_047300296.1
LRP2	XM_011511184.3	c.2811C>T	p.Ser937Ser	splice_region_variant, synonymous_variant	Exon 16 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.5100C>T	p.Ser1700Ser	splice_region_variant, synonymous_variant	Exon 31 of 79		NM_004525.3	ENSP00000496870.1

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

GnomAD2 exomes AF: 0.122 AC: 30634 AN: 250754 AF XY: 0.115

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 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

African (AFR) AF: 0.395 AC: 13220 AN: 33452

American (AMR) AF: 0.166 AC: 7410 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 4244 AN: 26124

East Asian (EAS) AF: 0.0788 AC: 3128 AN: 39688

South Asian (SAS) AF: 0.0890 AC: 7679 AN: 86254

European-Finnish (FIN) AF: 0.0469 AC: 2503 AN: 53400

Middle Eastern (MID) AF: 0.155 AC: 893 AN: 5754

European-Non Finnish (NFE) AF: 0.103 AC: 114799 AN: 1111732

Other (OTH) AF: 0.128 AC: 7698 AN: 60364

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

African (AFR) AF: 0.383 AC: 15859 AN: 41420

American (AMR) AF: 0.188 AC: 2877 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 540 AN: 3466

East Asian (EAS) AF: 0.0550 AC: 284 AN: 5168

South Asian (SAS) AF: 0.0763 AC: 367 AN: 4812

European-Finnish (FIN) AF: 0.0417 AC: 442 AN: 10598

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7089 AN: 68010

Other (OTH) AF: 0.184 AC: 389 AN: 2110

Alfa AF: 0.127 Hom.: 5413

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

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

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.38
DANN	Benign	0.40
PhyloP100		0.14
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2302694; hg19: chr2-170088351; COSMIC: COSV55553497;