2-169127752-A-ATT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_004525.3(LRP2):c.*910_*911insAA 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 0.018 (45 hom., cov: 0)
  • Exomes 𝑓: 0.034 (0 hom.)
• Consequence: LRP2 NM_004525.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.306

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.018 (2663/148040) while in subpopulation NFE AF= 0.0247 (1656/66998). AF 95% confidence interval is 0.0237. There are 45 homozygotes in gnomad4. There are 1322 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.*910_*911insAA		3_prime_UTR_variant	79/79	ENST00000649046.1
LRP2	XM_011511183.4	c.*910_*911insAA		3_prime_UTR_variant	78/78
LRP2	XM_011511184.3	c.*910_*911insAA		3_prime_UTR_variant	64/64
LRP2	XM_047444340.1	c.*910_*911insAA		3_prime_UTR_variant	79/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.*910_*911insAA		3_prime_UTR_variant	79/79		NM_004525.3	P1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2663 AN: 147970 Hom.: 45 Cov.: 0

Gnomad AFR AF: 0.00704

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.00994

Gnomad EAS AF: 0.00159

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0331

Gnomad MID AF: 0.0162

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.00936

GnomAD4 exome AF: 0.0341 AC: 12 AN: 352 Hom.: 0 Cov.: 0 AF XY: 0.0327 AC XY: 7 AN XY: 214

Gnomad4 FIN exome AF: 0.0347

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0180 AC: 2663 AN: 148040 Hom.: 45 Cov.: 0 AF XY: 0.0184 AC XY: 1322 AN XY: 72024

Gnomad4 AFR AF: 0.00707

Gnomad4 AMR AF: 0.0138

Gnomad4 ASJ AF: 0.00994

Gnomad4 EAS AF: 0.00159

Gnomad4 SAS AF: 0.0173

Gnomad4 FIN AF: 0.0331

Gnomad4 NFE AF: 0.0247

Gnomad4 OTH AF: 0.00929

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

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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: rs11411235; hg19: chr2-169984262;