2-169183778-T-C

Variant names:

• chr2-169183778-T-C
• rs7588584
• NM_004525.3:c.9846-1459A>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.9846-1459A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 152,102 control chromosomes in the GnomAD database, including 38,714 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 0.71 (38714 hom., cov: 33)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.358
• Publications: 1 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.9846-1459A>G		intron_variant	Intron 50 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.9846-1459A>G		intron_variant	Intron 50 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.8922-1459A>G		intron_variant	Intron 50 of 78		XP_047300296.1
LRP2	XM_011511184.3	c.7557-1459A>G		intron_variant	Intron 35 of 63		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.9846-1459A>G		intron_variant	Intron 50 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000649153.1	n.744-1459A>G		intron_variant	Intron 2 of 29			ENSP00000497617.1

Frequencies

GnomAD3 genomes AF: 0.711 AC: 108090 AN: 151984 Hom.: 38672 Cov.: 33

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.764

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.478

Gnomad SAS AF: 0.808

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.717

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

GnomAD4 genome AF: 0.711 AC: 108192 AN: 152102 Hom.: 38714 Cov.: 33 AF XY: 0.710 AC XY: 52797 AN XY: 74340

African (AFR) AF: 0.751 AC: 31160 AN: 41496

American (AMR) AF: 0.764 AC: 11681 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 2344 AN: 3468

East Asian (EAS) AF: 0.478 AC: 2469 AN: 5160

South Asian (SAS) AF: 0.807 AC: 3889 AN: 4820

European-Finnish (FIN) AF: 0.626 AC: 6615 AN: 10574

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.701 AC: 47671 AN: 67986

Other (OTH) AF: 0.718 AC: 1515 AN: 2110

Alfa AF: 0.711 Hom.: 4859

Bravo AF: 0.718

Asia WGS AF: 0.665 AC: 2313 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.41
PhyloP100		-0.36
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: rs7588584; hg19: chr2-170040288;