chr2-169140499-G-A

Position:

chr2-169140499-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004525.3(LRP2):c.13155C>T(p.His4385=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,613,952 control chromosomes in the GnomAD database, including 738 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 375 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 363 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0810

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 2-169140499-G-A is Benign according to our data. Variant chr2-169140499-G-A is described in ClinVar as [Benign]. Clinvar id is 129504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.081 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRP2	NM_004525.3 linkuse as main transcript	c.13155C>T	p.His4385=	synonymous_variant	72/79	ENST00000649046.1
LRP2	XM_011511183.4 linkuse as main transcript	c.13026C>T	p.His4342=	synonymous_variant	71/78
LRP2	XM_047444340.1 linkuse as main transcript	c.12231C>T	p.His4077=	synonymous_variant	72/79
LRP2	XM_011511184.3 linkuse as main transcript	c.10866C>T	p.His3622=	synonymous_variant	57/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
LRP2	ENST00000649046.1 linkuse as main transcript	c.13155C>T	p.His4385=	synonymous_variant	72/79	NM_004525.3	P1
LRP2	ENST00000649153.1 linkuse as main transcript	c.4009-889C>T		intron_variant, NMD_transcript_variant
LRP2	ENST00000650252.1 linkuse as main transcript	c.*829C>T		3_prime_UTR_variant, NMD_transcript_variant	17/24

Frequencies

GnomAD3 genomes

AF:

0.0374

AC:

5691

AN:

152080

Hom.:

373

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0182

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000514

Gnomad OTH

AF:

0.0205

GnomAD3 exomes

AF:

0.00984

AC:

2471

AN:

251098

Hom.:

129

AF XY:

0.00702

AC XY:

952

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.00593

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.00621

GnomAD4 exome

AF:

0.00400

AC:

5851

AN:

1461754

Hom.:

363

Cov.:

AF XY:

0.00350

AC XY:

2547

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.139

Gnomad4 AMR exome

AF:

0.00691

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000277

Gnomad4 OTH exome

AF:

0.00853

GnomAD4 genome

AF:

0.0375

AC:

5702

AN:

152198

Hom.:

375

Cov.:

AF XY:

0.0367

AC XY:

2734

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.129

Gnomad4 AMR

AF:

0.0180

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.0203

Alfa

AF:

0.0192

Hom.:

Bravo

AF:

0.0433

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2020	- -

not specified

Benign:2

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	Jul 15, 2021	- -
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 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

-0.45

CADD

Benign

0.79

DANN

Benign

0.72

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