rs143367996

chr2-169176579-G-Achr2-169176579-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004525.3(LRP2):c.10403C>T(p.Pro3468Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,614,014 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00089 (15 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 8.15

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRP2
• BP4: Computational evidence support a benign effect (MetaRNN=0.013441622).
• BP6: Variant 2-169176579-G-A is Benign according to our data. Variant chr2-169176579-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 332103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169176579-G-A is described in Lovd as [Benign]. Variant chr2-169176579-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00682 (1038/152156) while in subpopulation AFR AF= 0.0222 (923/41498). AF 95% confidence interval is 0.0211. There are 15 homozygotes in gnomad4. There are 507 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.10403C>T	p.Pro3468Leu	missense_variant	54/79	ENST00000649046.1
LRP2	XM_011511183.4	c.10403C>T	p.Pro3468Leu	missense_variant	54/78
LRP2	XM_047444340.1	c.9479C>T	p.Pro3160Leu	missense_variant	54/79
LRP2	XM_011511184.3	c.8114C>T	p.Pro2705Leu	missense_variant	39/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.10403C>T	p.Pro3468Leu	missense_variant	54/79		NM_004525.3	P1
LRP2	ENST00000649153.1	c.1304C>T	p.Pro435Leu	missense_variant, NMD_transcript_variant	6/30

Frequencies

GnomAD3 genomes AF: 0.00679 AC: 1033 AN: 152038 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00191 AC: 479 AN: 251384 Hom.: 5 AF XY: 0.00149 AC XY: 202 AN XY: 135860

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000893 AC: 1306 AN: 1461858 Hom.: 15 Cov.: 34 AF XY: 0.000804 AC XY: 585 AN XY: 727236

Gnomad4 AFR exome AF: 0.0234

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00682 AC: 1038 AN: 152156 Hom.: 15 Cov.: 33 AF XY: 0.00682 AC XY: 507 AN XY: 74376

Gnomad4 AFR AF: 0.0222

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00119 Hom.: 2

Bravo AF: 0.00779

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0243 AC: 107

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00229 AC: 278

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Donnai-Barrow syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 29, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
Polyphen		1.0	D;D
Vest4		0.51
MVP		0.75
MPC		0.40
ClinPred		0.099	T
GERP RS		5.0
Varity_R		0.72
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143367996; hg19: chr2-170033089; COSMIC: COSV104379196; COSMIC: COSV104379196;