2-169127533-TAAAAAAAA-TAAAAAAAAAAAAA

Variant names:

• chr2-169127533-T-TAAAAA
• rs3083240
• NM_004525.3:c.*1125_*1129dupTTTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_004525.3(LRP2):​c.*1125_*1129dupTTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 0)
  • Exomes 𝑓: 0.016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRP2 NM_004525.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.518

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 Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00118 (76/64528) while in subpopulation AFR AF= 0.00348 (49/14098). AF 95% confidence interval is 0.0027. There are 3 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.*1125_*1129dupTTTTT		3_prime_UTR_variant	Exon 79 of 79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.*1125_*1129dupTTTTT		3_prime_UTR_variant	Exon 78 of 78		XP_011509485.1
LRP2	XM_047444340.1	c.*1125_*1129dupTTTTT		3_prime_UTR_variant	Exon 79 of 79		XP_047300296.1
LRP2	XM_011511184.3	c.*1125_*1129dupTTTTT		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.*1125_*1129dupTTTTT		3_prime_UTR_variant	Exon 79 of 79		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 76 AN: 64538 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00348

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00267

Gnomad ASJ AF: 0.00188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000836

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000213

Gnomad OTH AF: 0.00127

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0159 AC: 2 AN: 126 Hom.: 0 Cov.: 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: 0.00118 AC: 76 AN: 64528 Hom.: 3 Cov.: 0 AF XY: 0.00106 AC XY: 30 AN XY: 28230

Gnomad4 AFR AF: 0.00348

Gnomad4 AMR AF: 0.00266

Gnomad4 ASJ AF: 0.00188

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000843

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000213

Gnomad4 OTH AF: 0.00127

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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;