Genetic Variant NM_004525.3:c.5099-125A>G (chr2-169231967-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004525.3(LRP2):c.5099-125A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,117,788 control chromosomes in the GnomAD database, including 158,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 25556 hom., cov: 31)

Exomes 𝑓: 0.51 ( 132932 hom. )

Consequence

LRP2
NM_004525.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.04

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 2-169231967-T-C is Benign according to our data. Variant chr2-169231967-T-C is described in ClinVar as [Benign]. Clinvar id is 1293114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.5099-125A>G	intron_variant	Intron 30 of 78	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.5099-125A>G	intron_variant	Intron 30 of 77		XP_011509485.1
LRP2	XM_047444340.1 link	c.4175-125A>G	intron_variant	Intron 30 of 78		XP_047300296.1
LRP2	XM_011511184.3 link	c.2810-125A>G	intron_variant	Intron 15 of 63		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1 link	c.5099-125A>G		intron_variant	Intron 30 of 78		NM_004525.3	ENSP00000496870.1		P98164

Frequencies

GnomAD3 genomes

AF:

0.568

AC:

86282

AN:

151900

Hom.:

25511

Cov.:

show subpopulations

Gnomad AFR

AF:

0.734

Gnomad AMI

AF:

0.482

Gnomad AMR

AF:

0.503

Gnomad ASJ

AF:

0.548

Gnomad EAS

AF:

0.532

Gnomad SAS

AF:

0.777

Gnomad FIN

AF:

0.402

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.497

Gnomad OTH

AF:

0.566

GnomAD4 exome

AF:

0.513

AC:

495554

AN:

965768

Hom.:

132932

AF XY:

0.524

AC XY:

258084

AN XY:

492646

show subpopulations

Gnomad4 AFR exome

AF:

0.736

Gnomad4 AMR exome

AF:

0.495

Gnomad4 ASJ exome

AF:

0.563

Gnomad4 EAS exome

AF:

0.538

Gnomad4 SAS exome

AF:

0.769

Gnomad4 FIN exome

AF:

0.409

Gnomad4 NFE exome

AF:

0.484

Gnomad4 OTH exome

AF:

0.538

GnomAD4 genome

AF:

0.568

AC:

86387

AN:

152020

Hom.:

25556

Cov.:

AF XY:

0.567

AC XY:

42107

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.734

Gnomad4 AMR

AF:

0.503

Gnomad4 ASJ

AF:

0.548

Gnomad4 EAS

AF:

0.532

Gnomad4 SAS

AF:

0.775

Gnomad4 FIN

AF:

0.402

Gnomad4 NFE

AF:

0.497

Gnomad4 OTH

AF:

0.571

Alfa

AF:

0.511

Hom.:

8341

Bravo

AF:

0.576

Asia WGS

AF:

0.691

AC:

2403

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

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

-0.92

CADD

Benign

0.045

DANN

Benign

0.30

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