rs2075252

chr2-169154475-T-Achr2-169154475-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_004525.3(LRP2):c.12280A>T(p.Lys4094Ter) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K4094K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRP2 NM_004525.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.87

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_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.12280A>T	p.Lys4094Ter	stop_gained	66/79	ENST00000649046.1
LRP2	XM_011511183.4	c.12151A>T	p.Lys4051Ter	stop_gained	65/78
LRP2	XM_047444340.1	c.11356A>T	p.Lys3786Ter	stop_gained	66/79
LRP2	XM_011511184.3	c.9991A>T	p.Lys3331Ter	stop_gained	51/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.12280A>T	p.Lys4094Ter	stop_gained	66/79		NM_004525.3	P1
LRP2	ENST00000649153.1	c.3181A>T	p.Lys1061Ter	stop_gained, NMD_transcript_variant	18/30
LRP2	ENST00000650252.1	c.1308A>T	p.Pro436=	synonymous_variant, NMD_transcript_variant	11/24

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460008 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 726446

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	42
Dann	Uncertain	0.99
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.85	D
MutationTaster	Benign	7.2e-31	P
Vest4		0.81
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2075252; hg19: chr2-170010985;