NM_004525.3:c.5099-740T>C

Variant names:

• chr2-169232582-A-G
• rs1362996
• NM_004525.3:c.5099-740T>C

Variant summary

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

The NM_004525.3(LRP2):​c.5099-740T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 152,044 control chromosomes in the GnomAD database, including 4,058 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 0.19 (4058 hom., cov: 31)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• Publications: 3 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.5099-740T>C		intron_variant	Intron 30 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.5099-740T>C		intron_variant	Intron 30 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.4175-740T>C		intron_variant	Intron 30 of 78		XP_047300296.1
LRP2	XM_011511184.3	c.2810-740T>C		intron_variant	Intron 15 of 63		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.5099-740T>C		intron_variant	Intron 30 of 78		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28683 AN: 151924 Hom.: 4054 Cov.: 31

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0554

Gnomad SAS AF: 0.0778

Gnomad FIN AF: 0.0382

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.189

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

GnomAD4 genome AF: 0.189 AC: 28724 AN: 152044 Hom.: 4058 Cov.: 31 AF XY: 0.183 AC XY: 13608 AN XY: 74366

African (AFR) AF: 0.400 AC: 16540 AN: 41382

American (AMR) AF: 0.191 AC: 2916 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 541 AN: 3464

East Asian (EAS) AF: 0.0555 AC: 287 AN: 5174

South Asian (SAS) AF: 0.0775 AC: 373 AN: 4814

European-Finnish (FIN) AF: 0.0382 AC: 405 AN: 10606

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7107 AN: 68000

Other (OTH) AF: 0.187 AC: 396 AN: 2114

Alfa AF: 0.167 Hom.: 372

Bravo AF: 0.209

Asia WGS AF: 0.113 AC: 396 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.9
DANN	Benign	0.68
PhyloP100		1.3
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: rs1362996; hg19: chr2-170089092;