2-169289151-C-T

Position:

chr2-169289151-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_004525.3(LRP2):c.923-6G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00949 in 1,613,810 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0073 ( 15 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 183 hom. )

Consequence

LRP2
NM_004525.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00004351

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.0380

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 2-169289151-C-T is Benign according to our data. Variant chr2-169289151-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129545.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=2}. Variant chr2-169289151-C-T is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
LRP2	NM_004525.3 linkuse as main transcript	c.923-6G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4 linkuse as main transcript	c.923-6G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		XP_011509485.1
LRP2	XM_047444340.1 linkuse as main transcript	c.-2-6G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 linkuse as main transcript	c.923-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_004525.3	ENSP00000496870	P1
LRP2	ENST00000443831.1 linkuse as main transcript	c.923-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000409813

Frequencies

GnomAD3 genomes

AF:

0.00736

AC:

1119

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00765

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0368

Gnomad FIN

AF:

0.00302

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.00853

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.0114

AC:

2852

AN:

251208

Hom.:

AF XY:

0.0133

AC XY:

1810

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00758

Gnomad ASJ exome

AF:

0.0270

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0405

Gnomad FIN exome

AF:

0.00208

Gnomad NFE exome

AF:

0.00810

Gnomad OTH exome

AF:

0.0150

GnomAD4 exome

AF:

0.00972

AC:

14202

AN:

1461608

Hom.:

183

Cov.:

AF XY:

0.0109

AC XY:

7943

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.00161

Gnomad4 AMR exome

AF:

0.00783

Gnomad4 ASJ exome

AF:

0.0287

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0401

Gnomad4 FIN exome

AF:

0.00219

Gnomad4 NFE exome

AF:

0.00757

Gnomad4 OTH exome

AF:

0.0120

GnomAD4 genome

AF:

0.00730

AC:

1111

AN:

152202

Hom.:

Cov.:

AF XY:

0.00799

AC XY:

595

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00152

Gnomad4 AMR

AF:

0.00764

Gnomad4 ASJ

AF:

0.0311

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0360

Gnomad4 FIN

AF:

0.00302

Gnomad4 NFE

AF:

0.00853

Gnomad4 OTH

AF:

0.00994

Alfa

AF:

0.00878

Hom.:

Bravo

AF:

0.00658

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0120

EpiControl

AF:

0.0116

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 18, 2014	- -

Donnai-Barrow syndrome

Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

2.4

DANN

Benign

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000044

dbscSNV1_RF

Benign

0.0080

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