2-169324795-A-G

Variant names:

• chr2-169324795-A-G
• rs2673177
• NM_004525.3:c.80-3911T>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.80-3911T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 151,936 control chromosomes in the GnomAD database, including 14,304 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 0.42 (14304 hom., cov: 31)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.296
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.80-3911T>C		intron_variant	Intron 1 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.80-3911T>C		intron_variant	Intron 1 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.-845-3911T>C		intron_variant	Intron 1 of 78		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.80-3911T>C		intron_variant	Intron 1 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.80-3911T>C		intron_variant	Intron 1 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63780 AN: 151818 Hom.: 14275 Cov.: 31

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.421

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

GnomAD4 genome AF: 0.420 AC: 63865 AN: 151936 Hom.: 14304 Cov.: 31 AF XY: 0.419 AC XY: 31107 AN XY: 74268

African (AFR) AF: 0.587 AC: 24314 AN: 41442

American (AMR) AF: 0.315 AC: 4813 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1579 AN: 3468

East Asian (EAS) AF: 0.373 AC: 1923 AN: 5156

South Asian (SAS) AF: 0.288 AC: 1386 AN: 4806

European-Finnish (FIN) AF: 0.338 AC: 3553 AN: 10526

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.368 AC: 25021 AN: 67956

Other (OTH) AF: 0.421 AC: 886 AN: 2106

Alfa AF: 0.387 Hom.: 40359

Bravo AF: 0.426

Asia WGS AF: 0.334 AC: 1164 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.24
DANN	Benign	0.23
PhyloP100		-0.30
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: rs2673177; hg19: chr2-170181305;