rs7600336

Variant names:

• chr2-169216851-C-T
• rs7600336
• NM_004525.3:c.5649-421G>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.5649-421G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 151,942 control chromosomes in the GnomAD database, including 20,656 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 0.51 (20656 hom., cov: 31)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.220
• Publications: 5 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.5649-421G>A		intron_variant	Intron 34 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.5649-421G>A		intron_variant	Intron 34 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.4725-421G>A		intron_variant	Intron 34 of 78		XP_047300296.1
LRP2	XM_011511184.3	c.3360-421G>A		intron_variant	Intron 19 of 63		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.5649-421G>A		intron_variant	Intron 34 of 78		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76836 AN: 151824 Hom.: 20623 Cov.: 31

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.515

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.508

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

GnomAD4 genome AF: 0.506 AC: 76923 AN: 151942 Hom.: 20656 Cov.: 31 AF XY: 0.504 AC XY: 37463 AN XY: 74258

African (AFR) AF: 0.688 AC: 28539 AN: 41462

American (AMR) AF: 0.412 AC: 6288 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 1783 AN: 3464

East Asian (EAS) AF: 0.473 AC: 2442 AN: 5168

South Asian (SAS) AF: 0.665 AC: 3209 AN: 4822

European-Finnish (FIN) AF: 0.373 AC: 3940 AN: 10550

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.429 AC: 29129 AN: 67912

Other (OTH) AF: 0.513 AC: 1081 AN: 2106

Alfa AF: 0.492 Hom.: 2434

Bravo AF: 0.513

Asia WGS AF: 0.607 AC: 2110 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.8
DANN	Benign	0.35
PhyloP100		0.22
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: rs7600336; hg19: chr2-170073361;