2-169290403-C-T

Variant names:

• chr2-169290403-C-T
• rs3770613
• NM_004525.3:c.922+442G>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.922+442G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 150,266 control chromosomes in the GnomAD database, including 18,332 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 0.48 (18332 hom., cov: 28)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.41
• Publications: 6 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.922+442G>A		intron_variant	Intron 8 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.922+442G>A		intron_variant	Intron 8 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.-3+442G>A		intron_variant	Intron 8 of 78		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.922+442G>A		intron_variant	Intron 8 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.922+442G>A		intron_variant	Intron 8 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 72552 AN: 150148 Hom.: 18316 Cov.: 28

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.623

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.670

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.520

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

GnomAD4 genome AF: 0.483 AC: 72594 AN: 150266 Hom.: 18332 Cov.: 28 AF XY: 0.484 AC XY: 35458 AN XY: 73264

African (AFR) AF: 0.361 AC: 14735 AN: 40788

American (AMR) AF: 0.415 AC: 6188 AN: 14894

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 2156 AN: 3462

East Asian (EAS) AF: 0.275 AC: 1380 AN: 5026

South Asian (SAS) AF: 0.541 AC: 2562 AN: 4734

European-Finnish (FIN) AF: 0.610 AC: 6276 AN: 10288

Middle Eastern (MID) AF: 0.669 AC: 194 AN: 290

European-Non Finnish (NFE) AF: 0.555 AC: 37639 AN: 67780

Other (OTH) AF: 0.517 AC: 1085 AN: 2098

Alfa AF: 0.526 Hom.: 26416

Bravo AF: 0.457

Asia WGS AF: 0.381 AC: 1326 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.52
DANN	Benign	0.42
PhyloP100		-1.4
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: rs3770613; hg19: chr2-170146913;