NM_004525.3:c.310+2108C>G

Variant names:

• chr2-169316654-G-C
• rs2544381
• NM_004525.3:c.310+2108C>G

Variant summary

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

The NM_004525.3(LRP2):​c.310+2108C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 151,980 control chromosomes in the GnomAD database, including 8,821 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 0.33 (8821 hom., cov: 31)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0440
• Publications: 6 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.310+2108C>G		intron_variant	Intron 3 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.310+2108C>G		intron_variant	Intron 3 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.-615+2108C>G		intron_variant	Intron 3 of 78		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.310+2108C>G		intron_variant	Intron 3 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.310+2108C>G		intron_variant	Intron 3 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50166 AN: 151862 Hom.: 8804 Cov.: 31

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.322

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

GnomAD4 genome AF: 0.330 AC: 50220 AN: 151980 Hom.: 8821 Cov.: 31 AF XY: 0.329 AC XY: 24440 AN XY: 74294

African (AFR) AF: 0.464 AC: 19231 AN: 41416

American (AMR) AF: 0.237 AC: 3618 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1148 AN: 3472

East Asian (EAS) AF: 0.277 AC: 1429 AN: 5166

South Asian (SAS) AF: 0.204 AC: 982 AN: 4816

European-Finnish (FIN) AF: 0.263 AC: 2778 AN: 10572

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20059 AN: 67962

Other (OTH) AF: 0.319 AC: 673 AN: 2112

Alfa AF: 0.317 Hom.: 998

Bravo AF: 0.334

Asia WGS AF: 0.230 AC: 800 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.97
DANN	Benign	0.72
PhyloP100		-0.044
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: rs2544381; hg19: chr2-170173164;