rs2229263

Positions:

• chr2-169318824-T-C

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.248A>G​(p.Asn83Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,613,762 control chromosomes in the GnomAD database, including 71,748 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8514 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63234 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.752

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 in gene, where missense usually causes diseases (based on misZ statistic), LRP2. . Trascript score misZ 4.5094 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, Stickler syndrome, Donnai-Barrow syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=9.2864037E-4).
• BP6: Variant 2-169318824-T-C is Benign according to our data. Variant chr2-169318824-T-C is described in ClinVar as [Benign]. Clinvar id is 129511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169318824-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.248A>G	p.Asn83Ser	missense_variant	3/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.248A>G	p.Asn83Ser	missense_variant	3/78		XP_011509485.1
LRP2	XM_047444340.1	c.-677A>G		5_prime_UTR_variant	3/79		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.248A>G	p.Asn83Ser	missense_variant	3/79		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.248A>G	p.Asn83Ser	missense_variant	3/23	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49520 AN: 151936 Hom.: 8498 Cov.: 32

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.320

GnomAD3 exomes AF: 0.272 AC: 68407 AN: 251368 Hom.: 10092 AF XY: 0.270 AC XY: 36742 AN XY: 135856

Gnomad AFR exome AF: 0.448

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.333

Gnomad EAS exome AF: 0.280

Gnomad SAS exome AF: 0.200

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.272

GnomAD4 exome AF: 0.290 AC: 423737 AN: 1461708 Hom.: 63234 Cov.: 40 AF XY: 0.287 AC XY: 208996 AN XY: 727162

Gnomad4 AFR exome AF: 0.452

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.334

Gnomad4 EAS exome AF: 0.289

Gnomad4 SAS exome AF: 0.198

Gnomad4 FIN exome AF: 0.260

Gnomad4 NFE exome AF: 0.297

Gnomad4 OTH exome AF: 0.293

GnomAD4 genome AF: 0.326 AC: 49573 AN: 152054 Hom.: 8514 Cov.: 32 AF XY: 0.325 AC XY: 24126 AN XY: 74330

Gnomad4 AFR AF: 0.448

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.331

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.204

Gnomad4 FIN AF: 0.263

Gnomad4 NFE AF: 0.295

Gnomad4 OTH AF: 0.317

Alfa AF: 0.306 Hom.: 12559

Bravo AF: 0.329

TwinsUK AF: 0.286 AC: 1059

ALSPAC AF: 0.294 AC: 1133

ESP6500AA AF: 0.435 AC: 1915

ESP6500EA AF: 0.293 AC: 2524

ExAC AF: 0.278 AC: 33762

Asia WGS AF: 0.228 AC: 796 AN: 3478

EpiCase AF: 0.304

EpiControl AF: 0.310

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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	Aug 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.072
DANN	Benign	0.29
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.50	.;T;T
MetaRNN	Benign	0.00093	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.080	N;N;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.060	.;N;N
REVEL	Benign	0.13
Sift	Benign	0.82	.;T;T
Sift4G	Benign	0.74	.;T;T
Polyphen		0.0030	B;B;B
Vest4		0.083, 0.038
MPC		0.19
ClinPred		0.0000096	T
GERP RS		-6.3
Varity_R		0.042
gMVP		0.23

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: rs2229263; hg19: chr2-170175334; COSMIC: COSV55541386;