2-169127752-A-AT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004525.3(LRP2):c.*910_*911insA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.72 (38694 hom., cov: 0)
  • Exomes 𝑓: 0.67 (74 hom.)
• Consequence: LRP2 NM_004525.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B: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 Benign. Variant got -10 ACMG points.

• BP6: Variant 2-169127752-A-AT is Benign according to our data. Variant chr2-169127752-A-AT is described in ClinVar as [Benign]. Clinvar id is 332052.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.723 AC: 106982 AN: 147972 Hom.: 38689 Cov.: 0

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.723

Gnomad AMR AF: 0.753

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.793

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.818

Gnomad NFE AF: 0.757

Gnomad OTH AF: 0.741

GnomAD4 exome AF: 0.675 AC: 247 AN: 366 Hom.: 74 Cov.: 0 AF XY: 0.659 AC XY: 149 AN XY: 226

Gnomad4 FIN exome AF: 0.675

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.723 AC: 107008 AN: 148042 Hom.: 38694 Cov.: 0 AF XY: 0.722 AC XY: 52014 AN XY: 72030

Gnomad4 AFR AF: 0.679

Gnomad4 AMR AF: 0.753

Gnomad4 ASJ AF: 0.679

Gnomad4 EAS AF: 0.497

Gnomad4 SAS AF: 0.792

Gnomad4 FIN AF: 0.715

Gnomad4 NFE AF: 0.757

Gnomad4 OTH AF: 0.741

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Donnai-Barrow syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs11411235; hg19: chr2-169984262;