rs4667596

Positions:

• chr2-169213662-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.6035G>A​(p.Arg2012Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,611,600 control chromosomes in the GnomAD database, including 650 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 0.018 (66 hom., cov: 32)
  • Exomes 𝑓: 0.021 (584 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.66

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=0.0019096136).
• BP6: Variant 2-169213662-C-T is Benign according to our data. Variant chr2-169213662-C-T is described in ClinVar as [Benign]. Clinvar id is 259419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169213662-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.6035G>A	p.Arg2012Lys	missense_variant	36/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.6035G>A	p.Arg2012Lys	missense_variant	36/78		XP_011509485.1
LRP2	XM_047444340.1	c.5111G>A	p.Arg1704Lys	missense_variant	36/79		XP_047300296.1
LRP2	XM_011511184.3	c.3746G>A	p.Arg1249Lys	missense_variant	21/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.6035G>A	p.Arg2012Lys	missense_variant	36/79		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2785 AN: 152140 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0577

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.0530

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00829

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0264 AC: 6577 AN: 248814 Hom.: 196 AF XY: 0.0235 AC XY: 3169 AN XY: 134672

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.0885

Gnomad ASJ exome AF: 0.00696

Gnomad EAS exome AF: 0.0461

Gnomad SAS exome AF: 0.0110

Gnomad FIN exome AF: 0.00836

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0219

GnomAD4 exome AF: 0.0214 AC: 31238 AN: 1459340 Hom.: 584 Cov.: 31 AF XY: 0.0206 AC XY: 14988 AN XY: 726136

Gnomad4 AFR exome AF: 0.00363

Gnomad4 AMR exome AF: 0.0849

Gnomad4 ASJ exome AF: 0.00720

Gnomad4 EAS exome AF: 0.0785

Gnomad4 SAS exome AF: 0.0128

Gnomad4 FIN exome AF: 0.00876

Gnomad4 NFE exome AF: 0.0190

Gnomad4 OTH exome AF: 0.0218

GnomAD4 genome AF: 0.0183 AC: 2792 AN: 152260 Hom.: 66 Cov.: 32 AF XY: 0.0184 AC XY: 1367 AN XY: 74444

Gnomad4 AFR AF: 0.00419

Gnomad4 AMR AF: 0.0579

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.0532

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.00829

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0185 Hom.: 64

Bravo AF: 0.0208

TwinsUK AF: 0.0186 AC: 69

ALSPAC AF: 0.0236 AC: 91

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0203 AC: 175

ExAC AF: 0.0234 AC: 2843

Asia WGS AF: 0.0370 AC: 129 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0154

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.057	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.43	.;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.13	.;N
REVEL	Benign	0.23
Sift	Benign	0.77	.;T
Sift4G	Uncertain	0.045	.;D
Polyphen		0.016	B;B
Vest4		0.023
MPC		0.25
ClinPred		0.012	T
GERP RS		2.2
Varity_R		0.042
gMVP		0.71

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: rs4667596; hg19: chr2-170070172; COSMIC: COSV55543335;