2-169307258-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004525.3(LRP2):c.427+23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,501,660 control chromosomes in the GnomAD database, including 33,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4343 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29114 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0840

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-169307258-T-C is Benign according to our data. Variant chr2-169307258-T-C is described in ClinVar as [Benign]. Clinvar id is 1180910.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.427+23A>G		intron_variant		ENST00000649046.1
LRP2	XM_011511183.4	c.427+23A>G		intron_variant
LRP2	XM_047444340.1	c.-498+23A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.427+23A>G		intron_variant			NM_004525.3	P1
LRP2	ENST00000443831.1	c.427+23A>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35064 AN: 151896 Hom.: 4339 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.0821

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.227

GnomAD3 exomes AF: 0.195 AC: 48877 AN: 251182 Hom.: 5205 AF XY: 0.195 AC XY: 26473 AN XY: 135758

Gnomad AFR exome AF: 0.317

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.257

Gnomad EAS exome AF: 0.0691

Gnomad SAS exome AF: 0.192

Gnomad FIN exome AF: 0.240

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.203 AC: 274433 AN: 1349646 Hom.: 29114 Cov.: 21 AF XY: 0.203 AC XY: 137784 AN XY: 677922

Gnomad4 AFR exome AF: 0.310

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.255

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.231 AC: 35084 AN: 152014 Hom.: 4343 Cov.: 32 AF XY: 0.231 AC XY: 17159 AN XY: 74310

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.250

Gnomad4 EAS AF: 0.0821

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.244

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.225

Alfa AF: 0.206 Hom.: 5322

Bravo AF: 0.227

Asia WGS AF: 0.131 AC: 458 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	3.8
Dann	Benign	0.56

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: rs2247506; hg19: chr2-170163768; COSMIC: COSV55539129;