2-169235885-A-G

Position:

chr2-169235885-A-G

Variant summary

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

The NM_004525.3(LRP2):c.4875T>C(p.Cys1625Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,613,596 control chromosomes in the GnomAD database, including 71,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 13586 hom., cov: 32)

Exomes 𝑓: 0.26 ( 57516 hom. )

Consequence

LRP2
NM_004525.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.75

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=-0.48).

BP6

Variant 2-169235885-A-G is Benign according to our data. Variant chr2-169235885-A-G is described in ClinVar as [Benign]. Clinvar id is 129526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169235885-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.75 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.645 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.4875T>C	p.Cys1625Cys	synonymous_variant	29/79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 linkuse as main transcript	c.4875T>C	p.Cys1625Cys	synonymous_variant	29/78		XP_011509485.1
LRP2	XM_047444340.1 linkuse as main transcript	c.3951T>C	p.Cys1317Cys	synonymous_variant	29/79		XP_047300296.1
LRP2	XM_011511184.3 linkuse as main transcript	c.2586T>C	p.Cys862Cys	synonymous_variant	14/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.4875T>C	p.Cys1625Cys	synonymous_variant	29/79		NM_004525.3	ENSP00000496870.1		P98164

Frequencies

GnomAD3 genomes

AF:

0.383

AC:

58261

AN:

151994

Hom.:

13564

Cov.:

show subpopulations

Gnomad AFR

AF:

0.651

Gnomad AMI

AF:

0.226

Gnomad AMR

AF:

0.437

Gnomad ASJ

AF:

0.348

Gnomad EAS

AF:

0.411

Gnomad SAS

AF:

0.369

Gnomad FIN

AF:

0.190

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.241

Gnomad OTH

AF:

0.391

GnomAD3 exomes

AF:

0.334

AC:

84008

AN:

251412

Hom.:

16365

AF XY:

0.324

AC XY:

43980

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.660

Gnomad AMR exome

AF:

0.486

Gnomad ASJ exome

AF:

0.381

Gnomad EAS exome

AF:

0.418

Gnomad SAS exome

AF:

0.368

Gnomad FIN exome

AF:

0.198

Gnomad NFE exome

AF:

0.241

Gnomad OTH exome

AF:

0.314

GnomAD4 exome

AF:

0.264

AC:

385576

AN:

1461484

Hom.:

57516

Cov.:

AF XY:

0.266

AC XY:

193589

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.663

Gnomad4 AMR exome

AF:

0.485

Gnomad4 ASJ exome

AF:

0.363

Gnomad4 EAS exome

AF:

0.390

Gnomad4 SAS exome

AF:

0.363

Gnomad4 FIN exome

AF:

0.202

Gnomad4 NFE exome

AF:

0.229

Gnomad4 OTH exome

AF:

0.297

GnomAD4 genome

AF:

0.384

AC:

58336

AN:

152112

Hom.:

13586

Cov.:

AF XY:

0.381

AC XY:

28308

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.651

Gnomad4 AMR

AF:

0.437

Gnomad4 ASJ

AF:

0.348

Gnomad4 EAS

AF:

0.412

Gnomad4 SAS

AF:

0.367

Gnomad4 FIN

AF:

0.190

Gnomad4 NFE

AF:

0.241

Gnomad4 OTH

AF:

0.390

Alfa

AF:

0.294

Hom.:

6658

Bravo

AF:

0.416

Asia WGS

AF:

0.402

AC:

1400

AN:

3478

EpiCase

AF:

0.252

EpiControl

AF:

0.258

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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	-	- -

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

-0.48

CADD

Benign

8.9

DANN

Benign

0.63

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