rs2239595

Positions:

• chr2-169233341-G-A

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.5098+70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,526,420 control chromosomes in the GnomAD database, including 20,719 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1927 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18792 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.979

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=-0.81).
• BP6: Variant 2-169233341-G-A is Benign according to our data. Variant chr2-169233341-G-A is described in ClinVar as [Benign]. Clinvar id is 1257304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.5098+70C>T		intron_variant		ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.5098+70C>T		intron_variant			XP_011509485.1
LRP2	XM_047444340.1	c.4174+70C>T		intron_variant			XP_047300296.1
LRP2	XM_011511184.3	c.2809+70C>T		intron_variant			XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.5098+70C>T		intron_variant			NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19964 AN: 152108 Hom.: 1929 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.158

GnomAD4 exome AF: 0.148 AC: 203685 AN: 1374194 Hom.: 18792 AF XY: 0.151 AC XY: 103760 AN XY: 688592

Gnomad4 AFR exome AF: 0.0280

Gnomad4 AMR exome AF: 0.377

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.346

Gnomad4 SAS exome AF: 0.237

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.131 AC: 19961 AN: 152226 Hom.: 1927 Cov.: 32 AF XY: 0.136 AC XY: 10093 AN XY: 74414

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.255

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.159

Alfa AF: 0.146 Hom.: 3288

Bravo AF: 0.139

Asia WGS AF: 0.278 AC: 965 AN: 3476

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.2
DANN	Benign	0.73

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: rs2239595; hg19: chr2-170089851; COSMIC: COSV55569878;