rs2075252

Variant names:

• chr2-169154475-T-C
• rs2075252
• NM_004525.3:c.12280A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-169154475-T-C
• chr2-169154475-T-G
• chr2-169154475-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004525.3(LRP2):​c.12280A>G​(p.Lys4094Glu) variant causes a missense change. The variant allele was found at a frequency of 0.762 in 1,610,506 control chromosomes in the GnomAD database, including 470,910 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K4094Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.79 (48286 hom., cov: 31)
  • Exomes 𝑓: 0.76 (422624 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.87
• Publications: 82 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Stickler syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• congenital heart disease

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.058307E-7).
• BP6: Variant 2-169154475-T-C is Benign according to our data. Variant chr2-169154475-T-C is described in ClinVar as Benign. ClinVar VariationId is 129500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.886 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.12280A>G	p.Lys4094Glu	missense	Exon 66 of 79	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.12280A>G	p.Lys4094Glu	missense	Exon 66 of 79	ENSP00000496870.1	P98164
	LRP2	ENST00000649153.1		n.3178A>G		non_coding_transcript_exon	Exon 18 of 30	ENSP00000497617.1	A0A3B3IT64
	LRP2	ENST00000650252.1		n.1308A>G		non_coding_transcript_exon	Exon 11 of 24	ENSP00000496887.1	A0A3B3IRR0

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120398 AN: 151984 Hom.: 48230 Cov.: 31

Gnomad AFR AF: 0.894

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.805

Gnomad ASJ AF: 0.739

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.791

GnomAD2 exomes AF: 0.761 AC: 191130 AN: 251178 AF XY: 0.765

Gnomad AFR exome AF: 0.898

Gnomad AMR exome AF: 0.800

Gnomad ASJ exome AF: 0.763

Gnomad EAS exome AF: 0.493

Gnomad FIN exome AF: 0.720

Gnomad NFE exome AF: 0.754

Gnomad OTH exome AF: 0.762

GnomAD4 exome AF: 0.758 AC: 1106038 AN: 1458404 Hom.: 422624 Cov.: 39 AF XY: 0.761 AC XY: 552486 AN XY: 725716

African (AFR) AF: 0.900 AC: 30048 AN: 33388

American (AMR) AF: 0.802 AC: 35814 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.756 AC: 19722 AN: 26090

East Asian (EAS) AF: 0.470 AC: 18615 AN: 39646

South Asian (SAS) AF: 0.855 AC: 73681 AN: 86194

European-Finnish (FIN) AF: 0.717 AC: 38311 AN: 53408

Middle Eastern (MID) AF: 0.813 AC: 4677 AN: 5754

European-Non Finnish (NFE) AF: 0.757 AC: 839533 AN: 1109008

Other (OTH) AF: 0.758 AC: 45637 AN: 60238

GnomAD4 genome AF: 0.792 AC: 120517 AN: 152102 Hom.: 48286 Cov.: 31 AF XY: 0.790 AC XY: 58735 AN XY: 74336

African (AFR) AF: 0.894 AC: 37135 AN: 41538

American (AMR) AF: 0.805 AC: 12299 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 2563 AN: 3470

East Asian (EAS) AF: 0.496 AC: 2554 AN: 5150

South Asian (SAS) AF: 0.856 AC: 4119 AN: 4810

European-Finnish (FIN) AF: 0.715 AC: 7567 AN: 10582

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.761 AC: 51703 AN: 67976

Other (OTH) AF: 0.792 AC: 1670 AN: 2108

Alfa AF: 0.764 Hom.: 201340

Bravo AF: 0.799

TwinsUK AF: 0.763 AC: 2829

ALSPAC AF: 0.734 AC: 2827

ESP6500AA AF: 0.885 AC: 3900

ESP6500EA AF: 0.758 AC: 6522

ExAC AF: 0.762 AC: 92507

Asia WGS AF: 0.726 AC: 2526 AN: 3478

EpiCase AF: 0.769

EpiControl AF: 0.771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Donnai-Barrow syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.34
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	9.1e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.3	N
PhyloP100		4.9
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.93	N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.94
ClinPred		0.0093	T
GERP RS		5.5
Varity_R		0.14
gMVP		0.71
Mutation Taster		=97/3	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: rs2075252; hg19: chr2-170010985; COSMIC: COSV55555478;