NM_004525.3:c.*1128_*1129delTT

Variant names:

• chr2-169127533-TAA-T
• rs3083240
• NM_004525.3:c.*1128_*1129delTT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004525.3(LRP2):​c.*1128_*1129delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 64,690 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 0)
  • Exomes 𝑓: 0.016 (0 hom.)
• Consequence: LRP2 NM_004525.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.293

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.*1128_*1129delTT		3_prime_UTR_variant	Exon 79 of 79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.*1128_*1129delTT		3_prime_UTR_variant	Exon 78 of 78		XP_011509485.1
LRP2	XM_047444340.1	c.*1128_*1129delTT		3_prime_UTR_variant	Exon 79 of 79		XP_047300296.1
LRP2	XM_011511184.3	c.*1128_*1129delTT		3_prime_UTR_variant	Exon 64 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046	c.*1128_*1129delTT		3_prime_UTR_variant	Exon 79 of 79		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.0000929 AC: 6 AN: 64564 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000205

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000267

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0159 AC: 2 AN: 126 Hom.: 0 AF XY: 0.0139 AC XY: 1 AN XY: 72

Gnomad4 FIN exome AF: 0.0164

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000929 AC: 6 AN: 64564 Hom.: 0 Cov.: 0 AF XY: 0.0000708 AC XY: 2 AN XY: 28238

Gnomad4 AFR AF: 0.000284

Gnomad4 AMR AF: 0.000205

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000267

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs3083240; hg19: chr2-169984043;