chr2-169300890-A-G

Variant names:

• chr2-169300890-A-G
• rs3914468
• NM_004525.3:c.428-6180T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004525.3(LRP2):​c.428-6180T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 151,998 control chromosomes in the GnomAD database, including 7,861 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 0.31 (7861 hom., cov: 31)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.643
• Publications: 3 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.428-6180T>C		intron_variant	Intron 4 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.428-6180T>C		intron_variant	Intron 4 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.-497-6180T>C		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.428-6180T>C		intron_variant	Intron 4 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.428-6180T>C		intron_variant	Intron 4 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46821 AN: 151880 Hom.: 7853 Cov.: 31

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.280

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

GnomAD4 genome AF: 0.308 AC: 46841 AN: 151998 Hom.: 7861 Cov.: 31 AF XY: 0.311 AC XY: 23111 AN XY: 74296

African (AFR) AF: 0.268 AC: 11124 AN: 41454

American (AMR) AF: 0.451 AC: 6884 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 627 AN: 3470

East Asian (EAS) AF: 0.607 AC: 3137 AN: 5168

South Asian (SAS) AF: 0.343 AC: 1653 AN: 4814

European-Finnish (FIN) AF: 0.284 AC: 3010 AN: 10592

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19336 AN: 67932

Other (OTH) AF: 0.280 AC: 592 AN: 2114

Alfa AF: 0.293 Hom.: 15188

Bravo AF: 0.324

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.0
DANN	Benign	0.45
PhyloP100		0.64
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: rs3914468; hg19: chr2-170157400;