rs34693334

chr2-169290992-C-Gchr2-169290992-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_004525.3(LRP2):c.775G>C(p.Gly259Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0651 in 1,613,654 control chromosomes in the GnomAD database, including 4,153 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G259S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.056 (353 hom., cov: 31)
  • Exomes 𝑓: 0.066 (3800 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.687

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=0.0017864704).
• BP6: Variant 2-169290992-C-G is Benign according to our data. Variant chr2-169290992-C-G is described in ClinVar as [Benign]. Clinvar id is 129539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169290992-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.775G>C	p.Gly259Arg	missense_variant	8/79	ENST00000649046.1
LRP2	XM_011511183.4	c.775G>C	p.Gly259Arg	missense_variant	8/78
LRP2	XM_047444340.1	c.-150G>C		5_prime_UTR_variant	8/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.775G>C	p.Gly259Arg	missense_variant	8/79		NM_004525.3	P1
LRP2	ENST00000443831.1	c.775G>C	p.Gly259Arg	missense_variant	8/23	2

Frequencies

GnomAD3 genomes AF: 0.0557 AC: 8475 AN: 152048 Hom.: 354 Cov.: 31

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0772

Gnomad FIN AF: 0.0874

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.0697

Gnomad OTH AF: 0.0621

GnomAD3 exomes AF: 0.0637 AC: 15985 AN: 250840 Hom.: 685 AF XY: 0.0665 AC XY: 9018 AN XY: 135530

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.0345

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.000979

Gnomad SAS exome AF: 0.0817

Gnomad FIN exome AF: 0.0832

Gnomad NFE exome AF: 0.0691

Gnomad OTH exome AF: 0.0827

GnomAD4 exome AF: 0.0661 AC: 96590 AN: 1461488 Hom.: 3800 Cov.: 32 AF XY: 0.0677 AC XY: 49187 AN XY: 727040

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.0367

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.0854

Gnomad4 FIN exome AF: 0.0837

Gnomad4 NFE exome AF: 0.0654

Gnomad4 OTH exome AF: 0.0707

GnomAD4 genome AF: 0.0557 AC: 8475 AN: 152166 Hom.: 353 Cov.: 31 AF XY: 0.0567 AC XY: 4214 AN XY: 74384

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.0492

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0773

Gnomad4 FIN AF: 0.0874

Gnomad4 NFE AF: 0.0697

Gnomad4 OTH AF: 0.0610

Alfa AF: 0.0698 Hom.: 388

Bravo AF: 0.0510

TwinsUK AF: 0.0677 AC: 251

ALSPAC AF: 0.0636 AC: 245

ESP6500AA AF: 0.0254 AC: 112

ESP6500EA AF: 0.0707 AC: 608

ExAC AF: 0.0630 AC: 7655

Asia WGS AF: 0.0340 AC: 119 AN: 3478

EpiCase AF: 0.0728

EpiControl AF: 0.0741

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Donnai-Barrow syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	9.4
Dann	Benign	0.44
DEOGEN2	Benign	0.068	T;T;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.20	N
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.34	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
Polyphen		0.013	B;B;B
Vest4		0.080, 0.039
MPC		0.28
ClinPred		0.0018	T
GERP RS		2.7
Varity_R		0.030
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs34693334; hg19: chr2-170147502; COSMIC: COSV55539090;