NM_004525.3:c.12591-169C>T

Variant names:

• chr2-169147128-G-A
• rs4667592
• NM_004525.3:c.12591-169C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004525.3(LRP2):​c.12591-169C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 151,974 control chromosomes in the GnomAD database, including 19,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.50 (19791 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.156
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-169147128-G-A is Benign according to our data. Variant chr2-169147128-G-A is described in ClinVar as Benign. ClinVar VariationId is 1231582.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.12591-169C>T		intron_variant	Intron 68 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.12462-169C>T		intron_variant	Intron 67 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.11667-169C>T		intron_variant	Intron 68 of 78		XP_047300296.1
LRP2	XM_011511184.3	c.10302-169C>T		intron_variant	Intron 53 of 63		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.12591-169C>T		intron_variant	Intron 68 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000649153.1	n.3489-169C>T		intron_variant	Intron 20 of 29			ENSP00000497617.1
LRP2	ENST00000650252.1	n.*302-169C>T		intron_variant	Intron 13 of 23			ENSP00000496887.1

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76436 AN: 151856 Hom.: 19776 Cov.: 32

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.494

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.503 AC: 76498 AN: 151974 Hom.: 19791 Cov.: 32 AF XY: 0.501 AC XY: 37209 AN XY: 74256

African (AFR) AF: 0.540 AC: 22367 AN: 41446

American (AMR) AF: 0.614 AC: 9389 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1608 AN: 3472

East Asian (EAS) AF: 0.116 AC: 599 AN: 5178

South Asian (SAS) AF: 0.461 AC: 2212 AN: 4800

European-Finnish (FIN) AF: 0.446 AC: 4705 AN: 10550

Middle Eastern (MID) AF: 0.510 AC: 149 AN: 292

European-Non Finnish (NFE) AF: 0.501 AC: 34031 AN: 67940

Other (OTH) AF: 0.493 AC: 1036 AN: 2100

Alfa AF: 0.482 Hom.: 8569

Bravo AF: 0.517

Asia WGS AF: 0.359 AC: 1252 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.91
CADD	Benign	2.0
DANN	Benign	0.49
PhyloP100		-0.16
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: rs4667592; hg19: chr2-170003638;