chr2-169231732-G-A

Position:

• chr2-169231732-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BS1 BS2

The NM_004525.3(LRP2):​c.5209C>T​(p.Leu1737Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,992 control chromosomes in the GnomAD database, including 3 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 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.786

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 -11 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=0.0062796474).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00125 (191/152242) while in subpopulation NFE AF= 0.00171 (116/68024). AF 95% confidence interval is 0.00145. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.5209C>T	p.Leu1737Phe	missense_variant	31/79	ENST00000649046.1
LRP2	XM_011511183.4	c.5209C>T	p.Leu1737Phe	missense_variant	31/78
LRP2	XM_047444340.1	c.4285C>T	p.Leu1429Phe	missense_variant	31/79
LRP2	XM_011511184.3	c.2920C>T	p.Leu974Phe	missense_variant	16/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.5209C>T	p.Leu1737Phe	missense_variant	31/79		NM_004525.3	P1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 191 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00120 AC: 300 AN: 250994 Hom.: 2 AF XY: 0.00120 AC XY: 163 AN XY: 135634

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00154 AC: 2256 AN: 1461750 Hom.: 3 Cov.: 31 AF XY: 0.00149 AC XY: 1083 AN XY: 727200

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00907

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000655

Gnomad4 NFE exome AF: 0.00162

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00125 AC: 191 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74440

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00171

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00122

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00105 AC: 127

EpiCase AF: 0.00147

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	LRP2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2020	This variant is associated with the following publications: (PMID: 25533962) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Donnai-Barrow syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 22, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 12, 2014

- -

LRP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 12, 2019

This variant is classified as 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	0.063
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	5.9
DANN	Benign	0.96
DEOGEN2	Benign	0.080	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.76	.;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.0063	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.010	.;N
REVEL	Benign	0.20
Sift	Benign	0.052	.;T
Sift4G	Uncertain	0.021	.;D
Polyphen		0.40	B;B
Vest4		0.036
MVP		0.19
MPC		0.30
ClinPred		0.016	T
GERP RS		-0.28
Varity_R		0.049
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs149469954; hg19: chr2-170088242; COSMIC: COSV55569619;