rs2239595

Variant names:

• chr2-169233341-G-A
• rs2239595
• NM_004525.3:c.5098+70C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000649046.1(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 ENST00000649046.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.979
• Publications: 12 publications found

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]

LRP2 Gene-Disease associations (from GenCC):

• Donnai-Barrow syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Stickler syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000649046.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.5098+70C>T		intron	N/A	NP_004516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.5098+70C>T		intron	N/A	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

African (AFR) AF: 0.0280 AC: 886 AN: 31642

American (AMR) AF: 0.377 AC: 16761 AN: 44408

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 4910 AN: 25532

East Asian (EAS) AF: 0.346 AC: 13596 AN: 39258

South Asian (SAS) AF: 0.237 AC: 19974 AN: 84228

European-Finnish (FIN) AF: 0.120 AC: 6382 AN: 53290

Middle Eastern (MID) AF: 0.197 AC: 1100 AN: 5594

European-Non Finnish (NFE) AF: 0.127 AC: 131124 AN: 1032736

Other (OTH) AF: 0.156 AC: 8952 AN: 57506

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

African (AFR) AF: 0.0321 AC: 1333 AN: 41564

American (AMR) AF: 0.268 AC: 4100 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 639 AN: 3472

East Asian (EAS) AF: 0.373 AC: 1933 AN: 5180

South Asian (SAS) AF: 0.255 AC: 1227 AN: 4814

European-Finnish (FIN) AF: 0.111 AC: 1172 AN: 10600

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9060 AN: 67988

Other (OTH) AF: 0.159 AC: 336 AN: 2114

Alfa AF: 0.139 Hom.: 5146

Bravo AF: 0.139

Asia WGS AF: 0.278 AC: 965 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.2
DANN	Benign	0.73
PhyloP100		-0.98
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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