rs3944004

chr2-169151712-A-Cchr2-169151712-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004525.3(LRP2):c.12462-686T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 152,088 control chromosomes in the GnomAD database, including 4,702 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 0.24 (4702 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.849

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.12462-686T>G		intron_variant		ENST00000649046.1
LRP2	XM_011511183.4	c.12333-686T>G		intron_variant
LRP2	XM_011511184.3	c.10173-686T>G		intron_variant
LRP2	XM_047444340.1	c.11538-686T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.12462-686T>G		intron_variant			NM_004525.3	P1
LRP2	ENST00000649153.1	c.3362-686T>G		intron_variant, NMD_transcript_variant
LRP2	ENST00000650252.1	c.*173-686T>G		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37064 AN: 151968 Hom.: 4698 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.262

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

GnomAD4 genome AF: 0.244 AC: 37092 AN: 152088 Hom.: 4702 Cov.: 32 AF XY: 0.245 AC XY: 18205 AN XY: 74324

Gnomad4 AFR AF: 0.275

Gnomad4 AMR AF: 0.166

Gnomad4 ASJ AF: 0.274

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.359

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.224

Gnomad4 OTH AF: 0.263

Alfa AF: 0.132 Hom.: 223

Bravo AF: 0.237

Asia WGS AF: 0.335 AC: 1163 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	13
Dann	Benign	0.89

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: rs3944004; hg19: chr2-170008222;