2-169307306-G-T

Position:

chr2-169307306-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004525.3(LRP2):c.402C>A(p.Pro134Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 1,612,032 control chromosomes in the GnomAD database, including 4,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.070 ( 427 hom., cov: 32)

Exomes 𝑓: 0.072 ( 4193 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.63

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 2-169307306-G-T is Benign according to our data. Variant chr2-169307306-G-T is described in ClinVar as [Benign]. Clinvar id is 129521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169307306-G-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.63 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.078 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3 linkuse as main transcript	c.402C>A	p.Pro134Pro	synonymous_variant	4/79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 linkuse as main transcript	c.402C>A	p.Pro134Pro	synonymous_variant	4/78		XP_011509485.1
LRP2	XM_047444340.1 linkuse as main transcript	c.-523C>A		5_prime_UTR_variant	4/79		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.402C>A	p.Pro134Pro	synonymous_variant	4/79		NM_004525.3	ENSP00000496870.1		P98164
LRP2	ENST00000443831.1 linkuse as main transcript	c.402C>A	p.Pro134Pro	synonymous_variant	4/23	2		ENSP00000409813.1		E9PC35

Frequencies

GnomAD3 genomes

AF:

0.0699

AC:

10637

AN:

152100

Hom.:

425

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0619

Gnomad AMI

AF:

0.228

Gnomad AMR

AF:

0.0752

Gnomad ASJ

AF:

0.0565

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0369

Gnomad FIN

AF:

0.0693

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0798

Gnomad OTH

AF:

0.0731

GnomAD3 exomes

AF:

0.0603

AC:

15137

AN:

251234

Hom.:

552

AF XY:

0.0613

AC XY:

8329

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.0649

Gnomad AMR exome

AF:

0.0480

Gnomad ASJ exome

AF:

0.0502

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0334

Gnomad FIN exome

AF:

0.0655

Gnomad NFE exome

AF:

0.0800

Gnomad OTH exome

AF:

0.0635

GnomAD4 exome

AF:

0.0720

AC:

105079

AN:

1459814

Hom.:

4193

Cov.:

AF XY:

0.0712

AC XY:

51697

AN XY:

726308

show subpopulations

Gnomad4 AFR exome

AF:

0.0612

Gnomad4 AMR exome

AF:

0.0491

Gnomad4 ASJ exome

AF:

0.0509

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0336

Gnomad4 FIN exome

AF:

0.0644

Gnomad4 NFE exome

AF:

0.0799

Gnomad4 OTH exome

AF:

0.0672

GnomAD4 genome

AF:

0.0699

AC:

10645

AN:

152218

Hom.:

427

Cov.:

AF XY:

0.0696

AC XY:

5181

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0620

Gnomad4 AMR

AF:

0.0751

Gnomad4 ASJ

AF:

0.0565

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0367

Gnomad4 FIN

AF:

0.0693

Gnomad4 NFE

AF:

0.0798

Gnomad4 OTH

AF:

0.0724

Alfa

AF:

0.0648

Hom.:

184

Bravo

AF:

0.0703

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0840

EpiControl

AF:

0.0888

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	clinical testing	GeneDx	Feb 21, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.056

DANN

Benign

0.42

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