rs147058423

Positions:

• chr2-169246785-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_004525.3(LRP2):​c.3110G>A​(p.Arg1037Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,614,196 control chromosomes in the GnomAD database, including 2 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.40

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRP2
• BP4: Computational evidence support a benign effect (MetaRNN=0.039171368).
• BP6: Variant 2-169246785-C-T is Benign according to our data. Variant chr2-169246785-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211395.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}. Variant chr2-169246785-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00123 (188/152312) while in subpopulation NFE AF= 0.00219 (149/68032). AF 95% confidence interval is 0.0019. There are 0 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.3110G>A	p.Arg1037Lys	missense_variant	21/79	ENST00000649046.1
LRP2	XM_011511183.4	c.3110G>A	p.Arg1037Lys	missense_variant	21/78
LRP2	XM_047444340.1	c.2186G>A	p.Arg729Lys	missense_variant	21/79
LRP2	XM_011511184.3	c.821G>A	p.Arg274Lys	missense_variant	6/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.3110G>A	p.Arg1037Lys	missense_variant	21/79		NM_004525.3	P1
LRP2	ENST00000443831.1	c.2699G>A	p.Arg900Lys	missense_variant	19/23	2

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00127 AC: 319 AN: 251480 Hom.: 0 AF XY: 0.00129 AC XY: 176 AN XY: 135910

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00244

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00196 AC: 2868 AN: 1461884 Hom.: 2 Cov.: 31 AF XY: 0.00196 AC XY: 1423 AN XY: 727242

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00125

Gnomad4 NFE exome AF: 0.00243

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00123 AC: 188 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.000967 AC XY: 72 AN XY: 74488

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00219

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00170 Hom.: 0

Bravo AF: 0.00122

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00151 AC: 183

EpiCase AF: 0.00142

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Donnai-Barrow syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 17, 2014

- -

LRP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 26, 2022

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	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T;T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.039	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.3	L;L;.
MutationTaster	Benign	0.75	N;N
PrimateAI	Benign	0.26	T
Polyphen		0.0030	B;B;B
Vest4		0.061, 0.11
MVP		0.49
MPC		0.27
ClinPred		0.013	T
GERP RS		2.7
Varity_R		0.10
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs147058423; hg19: chr2-170103295;