chr2-169271049-G-A

Position:

chr2-169271049-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004525.3(LRP2):c.2175C>T(p.Thr725Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,154 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 10 hom., cov: 31)

Exomes 𝑓: 0.011 ( 115 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.548

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:

LRP2 (HGNC:):

LRP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 2-169271049-G-A is Benign according to our data. Variant chr2-169271049-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.548 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00793 (1206/152124) while in subpopulation NFE AF= 0.0133 (903/67980). AF 95% confidence interval is 0.0126. There are 10 homozygotes in gnomad4. There are 577 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3 linkuse as main transcript	c.2175C>T	p.Thr725Thr	synonymous_variant	16/79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 linkuse as main transcript	c.2175C>T	p.Thr725Thr	synonymous_variant	16/78		XP_011509485.1
LRP2	XM_047444340.1 linkuse as main transcript	c.1251C>T	p.Thr417Thr	synonymous_variant	16/79		XP_047300296.1
LRP2	XM_011511184.3 linkuse as main transcript	c.31+621C>T		intron_variant			XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.2175C>T	p.Thr725Thr	synonymous_variant	16/79		NM_004525.3	ENSP00000496870.1	P98164
LRP2	ENST00000443831.1 linkuse as main transcript	c.1909+1878C>T		intron_variant		2		ENSP00000409813.1	E9PC35
LRP2	ENST00000493501.1 linkuse as main transcript	n.518C>T		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes

AF:

0.00793

AC:

1206

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00794

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00435

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00804

AC:

2016

AN:

250838

Hom.:

AF XY:

0.00786

AC XY:

1065

AN XY:

135550

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00607

Gnomad ASJ exome

AF:

0.00219

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00421

Gnomad NFE exome

AF:

0.0142

Gnomad OTH exome

AF:

0.00851

GnomAD4 exome

AF:

0.0112

AC:

16309

AN:

1461030

Hom.:

115

Cov.:

AF XY:

0.0109

AC XY:

7950

AN XY:

726826

show subpopulations

Gnomad4 AFR exome

AF:

0.00168

Gnomad4 AMR exome

AF:

0.00594

Gnomad4 ASJ exome

AF:

0.00199

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00472

Gnomad4 NFE exome

AF:

0.0136

Gnomad4 OTH exome

AF:

0.00979

GnomAD4 genome

AF:

0.00793

AC:

1206

AN:

152124

Hom.:

Cov.:

AF XY:

0.00776

AC XY:

577

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00236

Gnomad4 AMR

AF:

0.00793

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00435

Gnomad4 NFE

AF:

0.0133

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.0103

Hom.:

Bravo

AF:

0.00808

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0131

EpiControl

AF:

0.0137

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	LRP2: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Donnai-Barrow syndrome

Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

5.6

DANN

Benign

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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