rs142245618

chr2-169132617-A-G

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.13685T>C(p.Val4562Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,611,740 control chromosomes in the GnomAD database, including 15 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 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (15 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.580

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=0.0045801103).
• BP6: Variant 2-169132617-A-G is Benign according to our data. Variant chr2-169132617-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211393.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=1}. Variant chr2-169132617-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00191 (291/152314) while in subpopulation NFE AF= 0.00335 (228/68032). AF 95% confidence interval is 0.00299. There are 0 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.13685T>C	p.Val4562Ala	missense_variant	77/79	ENST00000649046.1
LRP2	XM_011511183.4	c.13556T>C	p.Val4519Ala	missense_variant	76/78
LRP2	XM_047444340.1	c.12761T>C	p.Val4254Ala	missense_variant	77/79
LRP2	XM_011511184.3	c.11396T>C	p.Val3799Ala	missense_variant	62/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.13685T>C	p.Val4562Ala	missense_variant	77/79		NM_004525.3	P1
LRP2	ENST00000491228.1	n.539T>C		non_coding_transcript_exon_variant	5/5	4
LRP2	ENST00000649153.1	c.*409T>C		3_prime_UTR_variant, NMD_transcript_variant	28/30
LRP2	ENST00000650252.1	c.*1359T>C		3_prime_UTR_variant, NMD_transcript_variant	22/24

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00189 AC: 475 AN: 251372 Hom.: 4 AF XY: 0.00187 AC XY: 254 AN XY: 135850

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000984

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00324

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00297 AC: 4336 AN: 1459426 Hom.: 15 Cov.: 29 AF XY: 0.00289 AC XY: 2098 AN XY: 726220

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.00170

Gnomad4 NFE exome AF: 0.00359

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74484

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00335

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00317 Hom.: 3

Bravo AF: 0.00189

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00185 AC: 225

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00255

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 25, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 23, 2014	- -

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 provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	LRP2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

LRP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2021

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	0.066
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	5.8
Dann	Benign	0.86
DEOGEN2	Benign	0.094	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.017	N
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
Polyphen		0.0010	B;B
Vest4		0.055
MVP		0.14
MPC		0.14
ClinPred		0.0023	T
GERP RS		-7.8
Varity_R		0.040
gMVP		0.26

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: rs142245618; hg19: chr2-169989127; COSMIC: COSV55556005;