rs4667596

Variant names:

• chr2-169213662-C-T
• rs4667596
• NM_004525.3:c.6035G>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.6035G>A​(p.Arg2012Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,611,600 control chromosomes in the GnomAD database, including 650 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (66 hom., cov: 32)
  • Exomes 𝑓: 0.021 (584 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.66
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019096136).
• BP6: Variant 2-169213662-C-T is Benign according to our data. Variant chr2-169213662-C-T is described in ClinVar as Benign. ClinVar VariationId is 259419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0548 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.6035G>A	p.Arg2012Lys	missense	Exon 36 of 79	NP_004516.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.6035G>A	p.Arg2012Lys	missense	Exon 36 of 79	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2785 AN: 152140 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0577

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.0530

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00829

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0264 AC: 6577 AN: 248814 AF XY: 0.0235

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.0885

Gnomad ASJ exome AF: 0.00696

Gnomad EAS exome AF: 0.0461

Gnomad FIN exome AF: 0.00836

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0219

GnomAD4 exome AF: 0.0214 AC: 31238 AN: 1459340 Hom.: 584 Cov.: 31 AF XY: 0.0206 AC XY: 14988 AN XY: 726136

African (AFR) AF: 0.00363 AC: 121 AN: 33378

American (AMR) AF: 0.0849 AC: 3793 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 188 AN: 26116

East Asian (EAS) AF: 0.0785 AC: 3116 AN: 39684

South Asian (SAS) AF: 0.0128 AC: 1102 AN: 86176

European-Finnish (FIN) AF: 0.00876 AC: 468 AN: 53412

Middle Eastern (MID) AF: 0.00988 AC: 48 AN: 4860

European-Non Finnish (NFE) AF: 0.0190 AC: 21088 AN: 1110784

Other (OTH) AF: 0.0218 AC: 1314 AN: 60230

GnomAD4 genome AF: 0.0183 AC: 2792 AN: 152260 Hom.: 66 Cov.: 32 AF XY: 0.0184 AC XY: 1367 AN XY: 74444

African (AFR) AF: 0.00419 AC: 174 AN: 41556

American (AMR) AF: 0.0579 AC: 886 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3466

East Asian (EAS) AF: 0.0532 AC: 275 AN: 5172

South Asian (SAS) AF: 0.0128 AC: 62 AN: 4826

European-Finnish (FIN) AF: 0.00829 AC: 88 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0179 AC: 1216 AN: 68016

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.0192 Hom.: 132

Bravo AF: 0.0208

TwinsUK AF: 0.0186 AC: 69

ALSPAC AF: 0.0236 AC: 91

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0203 AC: 175

ExAC AF: 0.0234 AC: 2843

Asia WGS AF: 0.0370 AC: 129 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0154

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Donnai-Barrow syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.7
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.23
Sift	Benign	0.77	T
Sift4G	Uncertain	0.045	D
Polyphen		0.016	B
Vest4		0.023
MPC		0.25
ClinPred		0.012	T
GERP RS		2.2
Varity_R		0.042
gMVP		0.71
Mutation Taster		=91/9	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: rs4667596; hg19: chr2-170070172; COSMIC: COSV55543335;