2-169127533-T-TAAA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_004525.3(LRP2):c.*1129_*1130insTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.062 (284 hom., cov: 0)
  • Exomes 𝑓: 0.032 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRP2 NM_004525.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.*1129_*1130insTTT		3_prime_UTR_variant	79/79	ENST00000649046.1
LRP2	XM_011511183.4	c.*1129_*1130insTTT		3_prime_UTR_variant	78/78
LRP2	XM_011511184.3	c.*1129_*1130insTTT		3_prime_UTR_variant	64/64
LRP2	XM_047444340.1	c.*1129_*1130insTTT		3_prime_UTR_variant	79/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.*1129_*1130insTTT		3_prime_UTR_variant	79/79		NM_004525.3	P1

Frequencies

GnomAD3 genomes AF: 0.0616 AC: 3938 AN: 63896 Hom.: 284 Cov.: 0

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0342

Gnomad ASJ AF: 0.0209

Gnomad EAS AF: 0.0171

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.0400

Gnomad NFE AF: 0.0417

Gnomad OTH AF: 0.0570

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0317 AC: 4 AN: 126 Hom.: 0 Cov.: 0 AF XY: 0.0278 AC XY: 2 AN XY: 72

Gnomad4 FIN exome AF: 0.0328

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0616 AC: 3938 AN: 63886 Hom.: 284 Cov.: 0 AF XY: 0.0621 AC XY: 1739 AN XY: 27988

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.0343

Gnomad4 ASJ AF: 0.0209

Gnomad4 EAS AF: 0.0171

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.0203

Gnomad4 NFE AF: 0.0417

Gnomad4 OTH AF: 0.0567

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Donnai-Barrow syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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;