chr2-169233424-C-T

Position:

chr2-169233424-C-T

Variant summary

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

The NM_004525.3(LRP2):c.5085G>A(p.Ser1695=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,614,094 control chromosomes in the GnomAD database, including 254 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1695S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0096 ( 12 hom., cov: 32)

Exomes 𝑓: 0.016 ( 242 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.788

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 2-169233424-C-T is Benign according to our data. Variant chr2-169233424-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169233424-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.788 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00963 (1466/152248) while in subpopulation NFE AF= 0.0163 (1112/68014). AF 95% confidence interval is 0.0156. There are 12 homozygotes in gnomad4. There are 648 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRP2	NM_004525.3 linkuse as main transcript	c.5085G>A	p.Ser1695=	synonymous_variant	30/79	ENST00000649046.1
LRP2	XM_011511183.4 linkuse as main transcript	c.5085G>A	p.Ser1695=	synonymous_variant	30/78
LRP2	XM_047444340.1 linkuse as main transcript	c.4161G>A	p.Ser1387=	synonymous_variant	30/79
LRP2	XM_011511184.3 linkuse as main transcript	c.2796G>A	p.Ser932=	synonymous_variant	15/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.5085G>A	p.Ser1695=	synonymous_variant	30/79		NM_004525.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00964

AC:

1466

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00304

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00818

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0163

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00897

AC:

2255

AN:

251456

Hom.:

AF XY:

0.00915

AC XY:

1244

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00567

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00516

Gnomad FIN exome

AF:

0.00573

Gnomad NFE exome

AF:

0.0148

Gnomad OTH exome

AF:

0.00782

GnomAD4 exome

AF:

0.0156

AC:

22748

AN:

1461846

Hom.:

242

Cov.:

AF XY:

0.0151

AC XY:

11003

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00242

Gnomad4 AMR exome

AF:

0.00588

Gnomad4 ASJ exome

AF:

0.00218

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00511

Gnomad4 FIN exome

AF:

0.00650

Gnomad4 NFE exome

AF:

0.0187

Gnomad4 OTH exome

AF:

0.0127

GnomAD4 genome

AF:

0.00963

AC:

1466

AN:

152248

Hom.:

Cov.:

AF XY:

0.00870

AC XY:

648

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00303

Gnomad4 AMR

AF:

0.00817

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00566

Gnomad4 NFE

AF:

0.0163

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0129

Hom.:

Bravo

AF:

0.00947

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0147

EpiControl

AF:

0.0145

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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

Donnai-Barrow syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.20

DANN

Benign

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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