rs146289506

chr2-169238246-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_004525.3(LRP2):c.4351G>T(p.Val1451Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00201 in 1,614,126 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (6 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 3.69

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRP2
• BP4: Computational evidence support a benign effect (MetaRNN=0.008307099).
• BP6: Variant 2-169238246-C-A is Benign according to our data. Variant chr2-169238246-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211398.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=5}. Variant chr2-169238246-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00158 (241/152278) while in subpopulation NFE AF= 0.00231 (157/68032). AF 95% confidence interval is 0.00201. There are 0 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.4351G>T	p.Val1451Phe	missense_variant	27/79	ENST00000649046.1
LRP2	XM_011511183.4	c.4351G>T	p.Val1451Phe	missense_variant	27/78
LRP2	XM_047444340.1	c.3427G>T	p.Val1143Phe	missense_variant	27/79
LRP2	XM_011511184.3	c.2062G>T	p.Val688Phe	missense_variant	12/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.4351G>T	p.Val1451Phe	missense_variant	27/79		NM_004525.3	P1

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 241 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00198 AC: 497 AN: 251424 Hom.: 0 AF XY: 0.00209 AC XY: 284 AN XY: 135876

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00300

Gnomad NFE exome AF: 0.00277

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00206 AC: 3010 AN: 1461848 Hom.: 6 Cov.: 32 AF XY: 0.00205 AC XY: 1488 AN XY: 727232

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00532

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00399

Gnomad4 NFE exome AF: 0.00224

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00158 AC: 241 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74450

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00259 Hom.: 2

Bravo AF: 0.00167

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00367

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LRP2: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 02, 2023	BS1 -

Donnai-Barrow syndrome Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 29, 2014

- -

LRP2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	13
Dann	Benign	0.70
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	0.51	D
PrimateAI	Benign	0.23	T
Polyphen		0.36	B;B
Vest4		0.22
MVP		0.33
MPC		0.31
ClinPred		0.019	T
GERP RS		2.8
Varity_R		0.092
gMVP		0.67

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: rs146289506; hg19: chr2-170094756; COSMIC: COSV55539117; COSMIC: COSV55539117;