2-169242963-T-C

Variant names:

Variant summary

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

The NM_004525.3(LRP2):c.3660A>G(p.Ala1220Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 1,609,298 control chromosomes in the GnomAD database, including 189,124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 20371 hom., cov: 32)

Exomes 𝑓: 0.47 ( 168753 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.757

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=-0.74).

BP6

Variant 2-169242963-T-C is Benign according to our data. Variant chr2-169242963-T-C is described in ClinVar as [Benign]. Clinvar id is 129519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169242963-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.757 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.3660A>G	p.Ala1220Ala	synonymous_variant	Exon 24 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.3660A>G	p.Ala1220Ala	synonymous_variant	Exon 24 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.2736A>G	p.Ala912Ala	synonymous_variant	Exon 24 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.1371A>G	p.Ala457Ala	synonymous_variant	Exon 9 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.3660A>G	p.Ala1220Ala	synonymous_variant	Exon 24 of 79		NM_004525.3	ENSP00000496870.1		P98164
LRP2	ENST00000443831.1 link	c.3249A>G	p.Ala1083Ala	synonymous_variant	Exon 22 of 23	2		ENSP00000409813.1		E9PC35

Frequencies

GnomAD3 genomes

AF:

0.511

AC:

77686

AN:

151912

Hom.:

20339

Cov.:

show subpopulations

Gnomad AFR

AF:

0.598

Gnomad AMI

AF:

0.401

Gnomad AMR

AF:

0.582

Gnomad ASJ

AF:

0.481

Gnomad EAS

AF:

0.476

Gnomad SAS

AF:

0.734

Gnomad FIN

AF:

0.383

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.453

Gnomad OTH

AF:

0.511

GnomAD3 exomes

AF:

0.524

AC:

131842

AN:

251448

Hom.:

36385

AF XY:

0.527

AC XY:

71671

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.606

Gnomad AMR exome

AF:

0.666

Gnomad ASJ exome

AF:

0.506

Gnomad EAS exome

AF:

0.475

Gnomad SAS exome

AF:

0.727

Gnomad FIN exome

AF:

0.386

Gnomad NFE exome

AF:

0.453

Gnomad OTH exome

AF:

0.484

GnomAD4 exome

AF:

0.473

AC:

689805

AN:

1457268

Hom.:

168753

Cov.:

AF XY:

0.480

AC XY:

348457

AN XY:

725222

show subpopulations

Gnomad4 AFR exome

AF:

0.599

Gnomad4 AMR exome

AF:

0.656

Gnomad4 ASJ exome

AF:

0.490

Gnomad4 EAS exome

AF:

0.456

Gnomad4 SAS exome

AF:

0.722

Gnomad4 FIN exome

AF:

0.387

Gnomad4 NFE exome

AF:

0.446

Gnomad4 OTH exome

AF:

0.486

GnomAD4 genome

AF:

0.512

AC:

77770

AN:

152030

Hom.:

20371

Cov.:

AF XY:

0.514

AC XY:

38177

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.598

Gnomad4 AMR

AF:

0.582

Gnomad4 ASJ

AF:

0.481

Gnomad4 EAS

AF:

0.476

Gnomad4 SAS

AF:

0.731

Gnomad4 FIN

AF:

0.383

Gnomad4 NFE

AF:

0.453

Gnomad4 OTH

AF:

0.517

Alfa

AF:

0.474

Hom.:

22630

Bravo

AF:

0.527

Asia WGS

AF:

0.637

AC:

2216

AN:

3478

EpiCase

AF:

0.459

EpiControl

AF:

0.460

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

3.7

DANN

Benign

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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