chr2-169127533-T-TA

Position:

• chr2-169127533-T-TA

Variant summary

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

The NM_004525.3(LRP2):​c.*1129dupT 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 0.17 (1339 hom., cov: 0)
  • Exomes 𝑓: 0.071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRP2 NM_004525.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.*1129dupT		3_prime_UTR_variant	79/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.*1129dupT		3_prime_UTR_variant	78/78		XP_011509485.1
LRP2	XM_047444340.1	c.*1129dupT		3_prime_UTR_variant	79/79		XP_047300296.1
LRP2	XM_011511184.3	c.*1129dupT		3_prime_UTR_variant	64/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046	c.*1129dupT		3_prime_UTR_variant	79/79		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.175 AC: 11277 AN: 64526 Hom.: 1337 Cov.: 0

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.0783

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.0936

Gnomad MID AF: 0.170

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.148

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0714 AC: 9 AN: 126 Hom.: 0 Cov.: 0 AF XY: 0.0833 AC XY: 6 AN XY: 72

Gnomad4 FIN exome AF: 0.0656

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.175 AC: 11281 AN: 64516 Hom.: 1339 Cov.: 0 AF XY: 0.176 AC XY: 4971 AN XY: 28220

Gnomad4 AFR AF: 0.306

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.0936

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.148

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Donnai-Barrow syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;