2-169217479-T-C

Variant names:

• chr2-169217479-T-C
• rs2300446
• NM_004525.3:c.5649-1049A>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.5649-1049A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 151,934 control chromosomes in the GnomAD database, including 19,066 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 0.49 (19066 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.792
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.5649-1049A>G		intron_variant	Intron 34 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.5649-1049A>G		intron_variant	Intron 34 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.4725-1049A>G		intron_variant	Intron 34 of 78		XP_047300296.1
LRP2	XM_011511184.3	c.3360-1049A>G		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.5649-1049A>G		intron_variant	Intron 34 of 78		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74401 AN: 151816 Hom.: 19042 Cov.: 32

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.493

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

GnomAD4 genome AF: 0.490 AC: 74471 AN: 151934 Hom.: 19066 Cov.: 32 AF XY: 0.489 AC XY: 36318 AN XY: 74260

African (AFR) AF: 0.635 AC: 26315 AN: 41438

American (AMR) AF: 0.402 AC: 6128 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1794 AN: 3468

East Asian (EAS) AF: 0.471 AC: 2431 AN: 5164

South Asian (SAS) AF: 0.665 AC: 3203 AN: 4818

European-Finnish (FIN) AF: 0.374 AC: 3946 AN: 10562

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29098 AN: 67934

Other (OTH) AF: 0.499 AC: 1049 AN: 2102

Alfa AF: 0.441 Hom.: 10700

Bravo AF: 0.494

Asia WGS AF: 0.601 AC: 2090 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	2.7
DANN	Benign	0.85
PhyloP100		-0.79
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: rs2300446; hg19: chr2-170073989;