NM_004525.3:c.3550+18T>G

Variant names:

• chr2-169243385-A-C
• rs2075255
• NM_004525.3:c.3550+18T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004525.3(LRP2):​c.3550+18T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 1,610,366 control chromosomes in the GnomAD database, including 206,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24806 hom., cov: 31)
  • Exomes 𝑓: 0.49 (182142 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.150
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-169243385-A-C is Benign according to our data. Variant chr2-169243385-A-C is described in ClinVar as Benign. ClinVar VariationId is 259414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.73 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.3550+18T>G		intron	N/A	NP_004516.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.3550+18T>G		intron	N/A	ENSP00000496870.1
	LRP2	ENST00000443831.1	TSL:2	c.3139+18T>G		intron	N/A	ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84540 AN: 151390 Hom.: 24756 Cov.: 31

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.753

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.556

GnomAD2 exomes AF: 0.548 AC: 137657 AN: 250986 AF XY: 0.550

Gnomad AFR exome AF: 0.738

Gnomad AMR exome AF: 0.678

Gnomad ASJ exome AF: 0.571

Gnomad EAS exome AF: 0.484

Gnomad FIN exome AF: 0.390

Gnomad NFE exome AF: 0.468

Gnomad OTH exome AF: 0.511

GnomAD4 exome AF: 0.491 AC: 715710 AN: 1458856 Hom.: 182142 Cov.: 35 AF XY: 0.498 AC XY: 361231 AN XY: 725820

African (AFR) AF: 0.737 AC: 24643 AN: 33444

American (AMR) AF: 0.670 AC: 29956 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 14472 AN: 26106

East Asian (EAS) AF: 0.461 AC: 18308 AN: 39674

South Asian (SAS) AF: 0.743 AC: 64035 AN: 86194

European-Finnish (FIN) AF: 0.393 AC: 20995 AN: 53374

Middle Eastern (MID) AF: 0.589 AC: 3389 AN: 5756

European-Non Finnish (NFE) AF: 0.459 AC: 508862 AN: 1109306

Other (OTH) AF: 0.515 AC: 31050 AN: 60298

GnomAD4 genome AF: 0.559 AC: 84649 AN: 151510 Hom.: 24806 Cov.: 31 AF XY: 0.560 AC XY: 41468 AN XY: 74040

African (AFR) AF: 0.729 AC: 30092 AN: 41258

American (AMR) AF: 0.606 AC: 9221 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1852 AN: 3464

East Asian (EAS) AF: 0.484 AC: 2486 AN: 5140

South Asian (SAS) AF: 0.750 AC: 3605 AN: 4806

European-Finnish (FIN) AF: 0.384 AC: 4034 AN: 10496

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31588 AN: 67830

Other (OTH) AF: 0.560 AC: 1181 AN: 2108

Alfa AF: 0.449 Hom.: 2345

Bravo AF: 0.580

Asia WGS AF: 0.660 AC: 2296 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Donnai-Barrow syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.13
DANN	Benign	0.32
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2075255; hg19: chr2-170099895;