rs2239602

Positions:

• chr2-169168830-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004525.3(LRP2):​c.11498-154G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.906 in 152,276 control chromosomes in the GnomAD database, including 62,638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.91 (62638 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.107

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 2-169168830-C-T is Benign according to our data. Variant chr2-169168830-C-T is described in ClinVar as [Benign]. Clinvar id is 1245516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.942 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.11498-154G>A		intron_variant		ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.11369-154G>A		intron_variant			XP_011509485.1
LRP2	XM_047444340.1	c.10574-154G>A		intron_variant			XP_047300296.1
LRP2	XM_011511184.3	c.9209-154G>A		intron_variant			XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.11498-154G>A		intron_variant			NM_004525.3	ENSP00000496870.1
LRP2	ENST00000649153.1	n.2396-154G>A		intron_variant				ENSP00000497617.1
LRP2	ENST00000650252.1	n.530-154G>A		intron_variant				ENSP00000496887.1

Frequencies

GnomAD3 genomes AF: 0.906 AC: 137834 AN: 152158 Hom.: 62582 Cov.: 32

Gnomad AFR AF: 0.950

Gnomad AMI AF: 0.900

Gnomad AMR AF: 0.927

Gnomad ASJ AF: 0.911

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.915

Gnomad FIN AF: 0.850

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.895

Gnomad OTH AF: 0.915

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.906 AC: 137949 AN: 152276 Hom.: 62638 Cov.: 32 AF XY: 0.903 AC XY: 67273 AN XY: 74470

Gnomad4 AFR AF: 0.950

Gnomad4 AMR AF: 0.927

Gnomad4 ASJ AF: 0.911

Gnomad4 EAS AF: 0.737

Gnomad4 SAS AF: 0.914

Gnomad4 FIN AF: 0.850

Gnomad4 NFE AF: 0.895

Gnomad4 OTH AF: 0.916

Alfa AF: 0.899 Hom.: 83019

Bravo AF: 0.909

Asia WGS AF: 0.859 AC: 2987 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.75
DANN	Benign	0.57

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: rs2239602; hg19: chr2-170025340; COSMIC: COSV104378311;