2-169191972-C-T

Position:

chr2-169191972-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_004525.3(LRP2):c.8892G>A(p.Arg2964=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00664 in 1,614,188 control chromosomes in the GnomAD database, including 50 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 0.0053 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0068 ( 47 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.230

Variant links:

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]

LRP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 2-169191972-C-T is Benign according to our data. Variant chr2-169191972-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211403.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}.

BP7

Synonymous conserved (PhyloP=0.23 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00528 (804/152334) while in subpopulation NFE AF= 0.00875 (595/68026). AF 95% confidence interval is 0.00817. There are 3 homozygotes in gnomad4. There are 357 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LRP2	NM_004525.3 linkuse as main transcript	c.8892G>A	p.Arg2964=	synonymous_variant	48/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4 linkuse as main transcript	c.8892G>A	p.Arg2964=	synonymous_variant	48/78		XP_011509485.1
LRP2	XM_047444340.1 linkuse as main transcript	c.7968G>A	p.Arg2656=	synonymous_variant	48/79		XP_047300296.1
LRP2	XM_011511184.3 linkuse as main transcript	c.6603G>A	p.Arg2201=	synonymous_variant	33/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.8892G>A	p.Arg2964=	synonymous_variant	48/79		NM_004525.3	ENSP00000496870	P1

Frequencies

GnomAD3 genomes

AF:

0.00528

AC:

804

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00875

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00493

AC:

1238

AN:

251222

Hom.:

AF XY:

0.00495

AC XY:

672

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00367

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.00286

Gnomad NFE exome

AF:

0.00830

Gnomad OTH exome

AF:

0.00555

GnomAD4 exome

AF:

0.00678

AC:

9911

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00679

AC XY:

4938

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00376

Gnomad4 ASJ exome

AF:

0.00138

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00131

Gnomad4 FIN exome

AF:

0.00391

Gnomad4 NFE exome

AF:

0.00812

Gnomad4 OTH exome

AF:

0.00513

GnomAD4 genome

AF:

0.00528

AC:

804

AN:

152334

Hom.:

Cov.:

AF XY:

0.00479

AC XY:

357

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00431

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00320

Gnomad4 NFE

AF:

0.00875

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00509

Hom.:

Bravo

AF:

0.00527

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00774

EpiControl

AF:

0.00777

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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	Jan 12, 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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	LRP2: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 26, 2014

- -

LRP2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 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

BayesDel_noAF

Benign

-0.42

CADD

Benign

1.9

DANN

Benign

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over