2-169206862-A-T

Position:

• chr2-169206862-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2 PP2 BP4_Strong BP6 BS1

The NM_004525.3(LRP2):​c.6858T>A​(p.Phe2286Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000973 in 1,614,202 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (1 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4
• Conservation: PhyloP100: 2.24

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.030703574).
• BP6: Variant 2-169206862-A-T is Benign according to our data. Variant chr2-169206862-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 546128.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}. Variant chr2-169206862-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000873 (133/152322) while in subpopulation AMR AF= 0.0017 (26/15298). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.6858T>A	p.Phe2286Leu	missense_variant	39/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.6858T>A	p.Phe2286Leu	missense_variant	39/78		XP_011509485.1
LRP2	XM_047444340.1	c.5934T>A	p.Phe1978Leu	missense_variant	39/79		XP_047300296.1
LRP2	XM_011511184.3	c.4569T>A	p.Phe1523Leu	missense_variant	24/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.6858T>A	p.Phe2286Leu	missense_variant	39/79		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000847 AC: 213 AN: 251354 Hom.: 0 AF XY: 0.000832 AC XY: 113 AN XY: 135862

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000983 AC: 1437 AN: 1461880 Hom.: 1 Cov.: 34 AF XY: 0.000989 AC XY: 719 AN XY: 727238

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00109

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.000873 AC: 133 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74486

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000918

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000782 AC: 95

EpiCase AF: 0.00164

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Donnai-Barrow syndrome Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2023	Identified as a germline variant in two cousins with childhood cancers, although several other variants were also identified and proposed as candidates for the cancer predisposition in this family (Derpoorter et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30350915) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 20, 2023	BS1_supporting -

LRP2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2024

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). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.051
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	.;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.031	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	.;D
REVEL	Uncertain	0.41
Sift	Benign	0.29	.;T
Sift4G	Uncertain	0.046	.;D
Polyphen		0.028	B;B
Vest4		0.29
MutPred		0.78		Gain of catalytic residue at F2286 (P = 0.1055);Gain of catalytic residue at F2286 (P = 0.1055);
MVP		0.57
MPC		0.29
ClinPred		0.032	T
GERP RS		3.4
Varity_R		0.38
gMVP		0.74

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: rs140918583; hg19: chr2-170063372; COSMIC: COSV104378868;