chr2-169196995-C-T

Position:

• chr2-169196995-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_004525.3(LRP2):​c.8614G>A​(p.Ala2872Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,604 control chromosomes in the GnomAD database, including 61,712 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5331 hom., cov: 33)
  • Exomes 𝑓: 0.27 (56381 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.28

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 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=2.2853743E-5).
• BP6: Variant 2-169196995-C-T is Benign according to our data. Variant chr2-169196995-C-T is described in ClinVar as [Benign]. Clinvar id is 129542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169196995-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.8614G>A	p.Ala2872Thr	missense_variant	46/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.8614G>A	p.Ala2872Thr	missense_variant	46/78		XP_011509485.1
LRP2	XM_047444340.1	c.7690G>A	p.Ala2564Thr	missense_variant	46/79		XP_047300296.1
LRP2	XM_011511184.3	c.6325G>A	p.Ala2109Thr	missense_variant	31/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.8614G>A	p.Ala2872Thr	missense_variant	46/79		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38454 AN: 152042 Hom.: 5331 Cov.: 33

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.544

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.234

GnomAD3 exomes AF: 0.267 AC: 67115 AN: 251132 Hom.: 10287 AF XY: 0.263 AC XY: 35695 AN XY: 135720

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.560

Gnomad SAS exome AF: 0.160

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.270 AC: 394385 AN: 1461444 Hom.: 56381 Cov.: 35 AF XY: 0.267 AC XY: 194018 AN XY: 727046

Gnomad4 AFR exome AF: 0.199

Gnomad4 AMR exome AF: 0.175

Gnomad4 ASJ exome AF: 0.280

Gnomad4 EAS exome AF: 0.560

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.356

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.271

GnomAD4 genome AF: 0.253 AC: 38461 AN: 152160 Hom.: 5331 Cov.: 33 AF XY: 0.254 AC XY: 18916 AN XY: 74374

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.543

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.359

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.231

Alfa AF: 0.271 Hom.: 10520

Bravo AF: 0.241

TwinsUK AF: 0.268 AC: 993

ALSPAC AF: 0.287 AC: 1105

ESP6500AA AF: 0.194 AC: 855

ESP6500EA AF: 0.263 AC: 2261

ExAC AF: 0.267 AC: 32470

Asia WGS AF: 0.312 AC: 1086 AN: 3478

EpiCase AF: 0.256

EpiControl AF: 0.247

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Donnai-Barrow syndrome Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.77
DANN	Benign	0.60
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.49	.;T
MetaRNN	Benign	0.000023	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.17	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.92	.;N
REVEL	Benign	0.23
Sift	Benign	0.96	.;T
Sift4G	Benign	0.94	.;T
Polyphen		0.0	B;B
Vest4		0.023
MPC		0.23
ClinPred		0.0087	T
GERP RS		-11
Varity_R		0.024
gMVP		0.29

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: rs2228171; hg19: chr2-170053505; COSMIC: COSV55542084;