2-169168688-GAA-GA

Variant names:

• chr2-169168688-GA-G
• rs143342962
• NM_004525.3:c.11498-13delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004525.3(LRP2):​c.11498-13delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0936 in 1,613,584 control chromosomes in the GnomAD database, including 7,947 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (530 hom., cov: 29)
  • Exomes 𝑓: 0.096 (7417 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.78
• Publications: 2 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Stickler syndrome

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

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• congenital heart disease

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-169168688-GA-G is Benign according to our data. Variant chr2-169168688-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.11498-13delT		intron	N/A	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.11498-13delT		intron	N/A	ENSP00000496870.1	P98164
	LRP2	ENST00000649153.1		n.2396-13delT		intron	N/A	ENSP00000497617.1	A0A3B3IT64
	LRP2	ENST00000650252.1		n.530-13delT		intron	N/A	ENSP00000496887.1	A0A3B3IRR0

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10903 AN: 152078 Hom.: 529 Cov.: 29

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0530

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.0905

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0636

GnomAD2 exomes AF: 0.0763 AC: 19145 AN: 250854 AF XY: 0.0777

Gnomad AFR exome AF: 0.0212

Gnomad AMR exome AF: 0.0357

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.00687

Gnomad FIN exome AF: 0.0908

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.0880

GnomAD4 exome AF: 0.0958 AC: 140067 AN: 1461388 Hom.: 7417 Cov.: 31 AF XY: 0.0951 AC XY: 69153 AN XY: 727032

African (AFR) AF: 0.0179 AC: 598 AN: 33460

American (AMR) AF: 0.0374 AC: 1671 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3947 AN: 26124

East Asian (EAS) AF: 0.00867 AC: 344 AN: 39686

South Asian (SAS) AF: 0.0518 AC: 4471 AN: 86250

European-Finnish (FIN) AF: 0.0900 AC: 4808 AN: 53406

Middle Eastern (MID) AF: 0.0827 AC: 477 AN: 5768

European-Non Finnish (NFE) AF: 0.106 AC: 118157 AN: 1111610

Other (OTH) AF: 0.0927 AC: 5594 AN: 60374

GnomAD4 genome AF: 0.0716 AC: 10903 AN: 152196 Hom.: 530 Cov.: 29 AF XY: 0.0696 AC XY: 5181 AN XY: 74400

African (AFR) AF: 0.0209 AC: 868 AN: 41548

American (AMR) AF: 0.0529 AC: 809 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 578 AN: 3468

East Asian (EAS) AF: 0.00850 AC: 44 AN: 5178

South Asian (SAS) AF: 0.0515 AC: 248 AN: 4812

European-Finnish (FIN) AF: 0.0905 AC: 958 AN: 10584

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7083 AN: 67996

Other (OTH) AF: 0.0649 AC: 137 AN: 2112

Alfa AF: 0.0650 Hom.: 74

Bravo AF: 0.0666

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Donnai-Barrow syndrome (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs143342962; hg19: chr2-170025198; COSMIC: COSV55540062;