chr2-169257160-G-C

Position:

• chr2-169257160-G-C

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.2603C>G​(p.Thr868Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000758 in 1,612,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin Lovd.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (0 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 4.63

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=0.0137916505).
• BP6: Variant 2-169257160-G-C is Benign according to our data. Variant chr2-169257160-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129512.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}. Variant chr2-169257160-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00223 (340/152216) while in subpopulation AFR AF= 0.00609 (253/41552). AF 95% confidence interval is 0.00547. There are 0 homozygotes in gnomad4. There are 153 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.2603C>G	p.Thr868Ser	missense_variant	18/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.2603C>G	p.Thr868Ser	missense_variant	18/78		XP_011509485.1
LRP2	XM_047444340.1	c.1679C>G	p.Thr560Ser	missense_variant	18/79		XP_047300296.1
LRP2	XM_011511184.3	c.314C>G	p.Thr105Ser	missense_variant	3/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.2603C>G	p.Thr868Ser	missense_variant	18/79		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.2192C>G	p.Thr731Ser	missense_variant	16/23	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00348

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.000996 AC: 250 AN: 250886 Hom.: 0 AF XY: 0.000863 AC XY: 117 AN XY: 135566

Gnomad AFR exome AF: 0.00714

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000494

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000604 AC: 883 AN: 1460720 Hom.: 0 Cov.: 32 AF XY: 0.000582 AC XY: 423 AN XY: 726692

Gnomad4 AFR exome AF: 0.00652

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.000959

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000425

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00206 AC XY: 153 AN XY: 74432

Gnomad4 AFR AF: 0.00609

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.000762 Hom.: 0

Bravo AF: 0.00325

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00104 AC: 126

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 13, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30900415) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Donnai-Barrow syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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. -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 16, 2022

Variant summary: LRP2 c.2603C>G (p.Thr868Ser) results in a conservative amino acid change located in the LDLR class B repeat (IPR000033) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 282278 control chromosomes (gnomAD), predominantly at a frequency of 0.0064 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in LRP2 causing Donnai Barrow Syndrome (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2603C>G in individuals affected with Donnai Barrow Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014: four classified the variant as of uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

LRP2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2019

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	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T;D
Eigen	Benign	-0.17
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	.;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	0.12	N;N;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	.;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.17	.;T;T
Sift4G	Benign	0.12	.;T;T
Polyphen		0.0010	B;B;B
Vest4		0.30, 0.27
MVP		0.43
MPC		0.23
ClinPred		0.033	T
GERP RS		4.7
Varity_R		0.17
gMVP		0.39

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: rs150752263; hg19: chr2-170113670; COSMIC: COSV104379429;