NM_004525.3:c.5099-125A>G

Variant names:

• chr2-169231967-T-C
• rs2302693
• NM_004525.3:c.5099-125A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.04
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• Donnai-Barrow syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Stickler syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.5099-125A>G		intron_variant	Intron 30 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.5099-125A>G		intron_variant	Intron 30 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.4175-125A>G		intron_variant	Intron 30 of 78		XP_047300296.1
LRP2	XM_011511184.3	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	c.5099-125A>G		intron_variant	Intron 30 of 78		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.568 AC: 86282 AN: 151900 Hom.: 25511 Cov.: 31

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

African (AFR) AF: 0.736 AC: 16121 AN: 21918

American (AMR) AF: 0.495 AC: 16356 AN: 33052

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 12147 AN: 21590

East Asian (EAS) AF: 0.538 AC: 17693 AN: 32896

South Asian (SAS) AF: 0.769 AC: 53596 AN: 69710

European-Finnish (FIN) AF: 0.409 AC: 19648 AN: 47990

Middle Eastern (MID) AF: 0.611 AC: 2318 AN: 3794

European-Non Finnish (NFE) AF: 0.484 AC: 334557 AN: 691844

Other (OTH) AF: 0.538 AC: 23118 AN: 42974

GnomAD4 genome AF: 0.568 AC: 86387 AN: 152020 Hom.: 25556 Cov.: 31 AF XY: 0.567 AC XY: 42107 AN XY: 74274

African (AFR) AF: 0.734 AC: 30446 AN: 41460

American (AMR) AF: 0.503 AC: 7689 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1897 AN: 3464

East Asian (EAS) AF: 0.532 AC: 2743 AN: 5158

South Asian (SAS) AF: 0.775 AC: 3734 AN: 4816

European-Finnish (FIN) AF: 0.402 AC: 4243 AN: 10558

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33804 AN: 67978

Other (OTH) AF: 0.571 AC: 1204 AN: 2108

Alfa AF: 0.513 Hom.: 9546

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

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
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2302693; hg19: chr2-170088477; COSMIC: COSV55574543;