rs144081819

chr2-169174129-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004525.3(LRP2):c.10804G>A(p.Ala3602Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,164 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3602V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0096 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (29 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.74

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=0.00956285).
• BP6: Variant 2-169174129-C-T is Benign according to our data. Variant chr2-169174129-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00965 (1469/152298) while in subpopulation AFR AF= 0.033 (1373/41558). AF 95% confidence interval is 0.0316. There are 22 homozygotes in gnomad4. There are 669 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.10804G>A	p.Ala3602Thr	missense_variant	56/79	ENST00000649046.1
LRP2	XM_011511183.4	c.10804G>A	p.Ala3602Thr	missense_variant	56/78
LRP2	XM_047444340.1	c.9880G>A	p.Ala3294Thr	missense_variant	56/79
LRP2	XM_011511184.3	c.8515G>A	p.Ala2839Thr	missense_variant	41/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.10804G>A	p.Ala3602Thr	missense_variant	56/79		NM_004525.3	P1
LRP2	ENST00000649153.1	c.1705G>A	p.Ala569Thr	missense_variant, NMD_transcript_variant	8/30

Frequencies

GnomAD3 genomes AF: 0.00959 AC: 1460 AN: 152180 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00251 AC: 631 AN: 251380 Hom.: 11 AF XY: 0.00183 AC XY: 248 AN XY: 135882

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00119 AC: 1743 AN: 1461866 Hom.: 29 Cov.: 32 AF XY: 0.00109 AC XY: 796 AN XY: 727230

Gnomad4 AFR exome AF: 0.0361

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000217

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00965 AC: 1469 AN: 152298 Hom.: 22 Cov.: 32 AF XY: 0.00898 AC XY: 669 AN XY: 74470

Gnomad4 AFR AF: 0.0330

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00172 Hom.: 9

Bravo AF: 0.0108

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0311 AC: 137

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00297 AC: 361

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Donnai-Barrow syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
MetaRNN	Benign	0.0096	T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.35	T
Polyphen		1.0	D;D
Vest4		0.27
MVP		0.52
MPC		0.26
ClinPred		0.018	T
GERP RS		4.5
Varity_R		0.072
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144081819; hg19: chr2-170030639; COSMIC: COSV55562343; COSMIC: COSV55562343;