NM_004525.3:c.4875T>C

Variant names:

• chr2-169235885-A-G
• rs2229267
• NM_004525.3:c.4875T>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.4875T>C​(p.Cys1625Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,613,596 control chromosomes in the GnomAD database, including 71,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (13586 hom., cov: 32)
  • Exomes 𝑓: 0.26 (57516 hom.)
• Consequence: LRP2 NM_004525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.75
• Publications: 24 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=-0.48).
• BP6: Variant 2-169235885-A-G is Benign according to our data. Variant chr2-169235885-A-G is described in ClinVar as Benign. ClinVar VariationId is 129526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.645 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.4875T>C	p.Cys1625Cys	synonymous	Exon 29 of 79	NP_004516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.4875T>C	p.Cys1625Cys	synonymous	Exon 29 of 79	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58261 AN: 151994 Hom.: 13564 Cov.: 32

Gnomad AFR AF: 0.651

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.391

GnomAD2 exomes AF: 0.334 AC: 84008 AN: 251412 AF XY: 0.324

Gnomad AFR exome AF: 0.660

Gnomad AMR exome AF: 0.486

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.418

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.314

GnomAD4 exome AF: 0.264 AC: 385576 AN: 1461484 Hom.: 57516 Cov.: 36 AF XY: 0.266 AC XY: 193589 AN XY: 727064

African (AFR) AF: 0.663 AC: 22203 AN: 33474

American (AMR) AF: 0.485 AC: 21692 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 9480 AN: 26132

East Asian (EAS) AF: 0.390 AC: 15502 AN: 39698

South Asian (SAS) AF: 0.363 AC: 31273 AN: 86244

European-Finnish (FIN) AF: 0.202 AC: 10808 AN: 53406

Middle Eastern (MID) AF: 0.368 AC: 2122 AN: 5766

European-Non Finnish (NFE) AF: 0.229 AC: 254554 AN: 1111658

Other (OTH) AF: 0.297 AC: 17942 AN: 60382

GnomAD4 genome AF: 0.384 AC: 58336 AN: 152112 Hom.: 13586 Cov.: 32 AF XY: 0.381 AC XY: 28308 AN XY: 74360

African (AFR) AF: 0.651 AC: 27016 AN: 41484

American (AMR) AF: 0.437 AC: 6670 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1209 AN: 3472

East Asian (EAS) AF: 0.412 AC: 2127 AN: 5166

South Asian (SAS) AF: 0.367 AC: 1768 AN: 4816

European-Finnish (FIN) AF: 0.190 AC: 2011 AN: 10594

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16393 AN: 67984

Other (OTH) AF: 0.390 AC: 824 AN: 2114

Alfa AF: 0.311 Hom.: 10165

Bravo AF: 0.416

Asia WGS AF: 0.402 AC: 1400 AN: 3478

EpiCase AF: 0.252

EpiControl AF: 0.258

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Donnai-Barrow syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.9
DANN	Benign	0.63
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2229267; hg19: chr2-170092395; COSMIC: COSV55548411; COSMIC: COSV55548411;