NM_004525.3:c.13728+713T>A

Variant names:

• chr2-169131861-A-T
• rs1003456
• NM_004525.3:c.13728+713T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004525.3(LRP2):​c.13728+713T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 152,246 control chromosomes in the GnomAD database, including 48,620 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.80 (48620 hom., cov: 33)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.141
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.806 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.13728+713T>A		intron	N/A	NP_004516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.13728+713T>A		intron	N/A	ENSP00000496870.1
	LRP2	ENST00000649153.1		n.*452+713T>A		intron	N/A	ENSP00000497617.1
	LRP2	ENST00000650252.1		n.*1402+713T>A		intron	N/A	ENSP00000496887.1

Frequencies

GnomAD3 genomes AF: 0.797 AC: 121201 AN: 152128 Hom.: 48581 Cov.: 33

Gnomad AFR AF: 0.814

Gnomad AMI AF: 0.784

Gnomad AMR AF: 0.801

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.821

Gnomad FIN AF: 0.793

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.811

Gnomad OTH AF: 0.796

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.797 AC: 121293 AN: 152246 Hom.: 48620 Cov.: 33 AF XY: 0.795 AC XY: 59190 AN XY: 74438

African (AFR) AF: 0.814 AC: 33800 AN: 41544

American (AMR) AF: 0.800 AC: 12237 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2449 AN: 3470

East Asian (EAS) AF: 0.504 AC: 2611 AN: 5178

South Asian (SAS) AF: 0.821 AC: 3965 AN: 4830

European-Finnish (FIN) AF: 0.793 AC: 8407 AN: 10600

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.811 AC: 55175 AN: 68016

Other (OTH) AF: 0.795 AC: 1682 AN: 2116

Alfa AF: 0.805 Hom.: 6113

Bravo AF: 0.795

Asia WGS AF: 0.682 AC: 2372 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.2
DANN	Benign	0.55
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1003456; hg19: chr2-169988371;