2-169297016-C-T

Variant names:

• chr2-169297016-C-T
• rs2673164
• NM_004525.3:c.428-2306G>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.428-2306G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 151,950 control chromosomes in the GnomAD database, including 30,711 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 0.62 (30711 hom., cov: 31)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0980
• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.428-2306G>A		intron_variant	Intron 4 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.428-2306G>A		intron_variant	Intron 4 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.-497-2306G>A		intron_variant	Intron 4 of 78		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.428-2306G>A		intron_variant	Intron 4 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.428-2306G>A		intron_variant	Intron 4 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.621 AC: 94296 AN: 151830 Hom.: 30714 Cov.: 31

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.751

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.764

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.635

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

GnomAD4 genome AF: 0.621 AC: 94323 AN: 151950 Hom.: 30711 Cov.: 31 AF XY: 0.621 AC XY: 46123 AN XY: 74306

African (AFR) AF: 0.425 AC: 17589 AN: 41422

American (AMR) AF: 0.512 AC: 7808 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.751 AC: 2605 AN: 3470

East Asian (EAS) AF: 0.560 AC: 2880 AN: 5144

South Asian (SAS) AF: 0.723 AC: 3487 AN: 4820

European-Finnish (FIN) AF: 0.739 AC: 7808 AN: 10566

Middle Eastern (MID) AF: 0.764 AC: 223 AN: 292

European-Non Finnish (NFE) AF: 0.735 AC: 49985 AN: 67972

Other (OTH) AF: 0.637 AC: 1341 AN: 2106

Alfa AF: 0.689 Hom.: 121793

Bravo AF: 0.590

Asia WGS AF: 0.611 AC: 2126 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.1
DANN	Benign	0.50
PhyloP100		0.098
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: rs2673164; hg19: chr2-170153526;