2-169301446-G-T

Variant names:

• chr2-169301446-G-T
• rs2892802
• NM_004525.3:c.427+5835C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004525.3(LRP2):​c.427+5835C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 151,132 control chromosomes in the GnomAD database, including 975 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (975 hom., cov: 30)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.342
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004525.3. 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.427+5835C>A		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.427+5835C>A		intron	N/A	ENSP00000496870.1
	LRP2	ENST00000443831.1	TSL:2	c.427+5835C>A		intron	N/A	ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16182 AN: 151054 Hom.: 974 Cov.: 30

Gnomad AFR AF: 0.0650

Gnomad AMI AF: 0.0637

Gnomad AMR AF: 0.0871

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.0706

Gnomad SAS AF: 0.0890

Gnomad FIN AF: 0.0964

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.113

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

GnomAD4 genome AF: 0.107 AC: 16175 AN: 151132 Hom.: 975 Cov.: 30 AF XY: 0.104 AC XY: 7639 AN XY: 73748

African (AFR) AF: 0.0650 AC: 2676 AN: 41196

American (AMR) AF: 0.0870 AC: 1319 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 460 AN: 3458

East Asian (EAS) AF: 0.0708 AC: 364 AN: 5144

South Asian (SAS) AF: 0.0885 AC: 422 AN: 4766

European-Finnish (FIN) AF: 0.0964 AC: 993 AN: 10300

Middle Eastern (MID) AF: 0.117 AC: 34 AN: 290

European-Non Finnish (NFE) AF: 0.142 AC: 9616 AN: 67820

Other (OTH) AF: 0.111 AC: 233 AN: 2090

Alfa AF: 0.127 Hom.: 1513

Bravo AF: 0.106

Asia WGS AF: 0.0750 AC: 259 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.8
DANN	Benign	0.77
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2892802; hg19: chr2-170157956;