chr2-169360358-T-C

Variant names:

• chr2-169360358-T-C
• rs3845732
• NM_004525.3:c.79+1963A>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.79+1963A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.678 in 151,976 control chromosomes in the GnomAD database, including 37,462 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 0.68 (37462 hom., cov: 30)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.153
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.79+1963A>G		intron_variant	Intron 1 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.79+1963A>G		intron_variant	Intron 1 of 77		XP_011509485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.79+1963A>G		intron_variant	Intron 1 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.79+1963A>G		intron_variant	Intron 1 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103056 AN: 151858 Hom.: 37450 Cov.: 30

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.761

Gnomad AMR AF: 0.698

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.860

Gnomad MID AF: 0.675

Gnomad NFE AF: 0.814

Gnomad OTH AF: 0.685

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

GnomAD4 genome AF: 0.678 AC: 103086 AN: 151976 Hom.: 37462 Cov.: 30 AF XY: 0.678 AC XY: 50368 AN XY: 74286

African (AFR) AF: 0.423 AC: 17501 AN: 41414

American (AMR) AF: 0.699 AC: 10664 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 2381 AN: 3468

East Asian (EAS) AF: 0.409 AC: 2107 AN: 5156

South Asian (SAS) AF: 0.763 AC: 3678 AN: 4818

European-Finnish (FIN) AF: 0.860 AC: 9090 AN: 10572

Middle Eastern (MID) AF: 0.678 AC: 198 AN: 292

European-Non Finnish (NFE) AF: 0.814 AC: 55330 AN: 67982

Other (OTH) AF: 0.687 AC: 1446 AN: 2106

Alfa AF: 0.774 Hom.: 71381

Bravo AF: 0.651

Asia WGS AF: 0.613 AC: 2133 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.7
DANN	Benign	0.82
PhyloP100		0.15
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: rs3845732; hg19: chr2-170216868;