rs2241190

Variant names:

• chr2-169259078-T-C
• rs2241190
• NM_004525.3:c.2460A>G
• LRP2 p.Thr820Thr

Your query was ambiguous. Multiple possible variants found:

• chr2-169259078-T-C
• chr2-169259078-T-A
• chr2-169259078-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004525.3(LRP2):​c.2460A>G​(p.Thr820Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 1,612,380 control chromosomes in the GnomAD database, including 206,412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23672 hom., cov: 30)
  • Exomes 𝑓: 0.49 (182740 hom.)
• Consequence: LRP2 NM_004525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.419
• Publications: 31 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-169259078-T-C is Benign according to our data. Variant chr2-169259078-T-C is described in ClinVar as Benign. ClinVar VariationId is 129510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.419 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.732 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.2460A>G	p.Thr820Thr	synonymous	Exon 17 of 79	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.2460A>G	p.Thr820Thr	synonymous	Exon 17 of 79	ENSP00000496870.1	P98164
	LRP2	ENST00000443831.1	TSL:2	c.2049A>G	p.Thr683Thr	synonymous	Exon 15 of 23	ENSP00000409813.1	E9PC35

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83113 AN: 151526 Hom.: 23636 Cov.: 30

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.478

Gnomad SAS AF: 0.755

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.550

GnomAD2 exomes AF: 0.546 AC: 137151 AN: 251078 AF XY: 0.548

Gnomad AFR exome AF: 0.694

Gnomad AMR exome AF: 0.686

Gnomad ASJ exome AF: 0.543

Gnomad EAS exome AF: 0.476

Gnomad FIN exome AF: 0.391

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.492 AC: 718665 AN: 1460736 Hom.: 182740 Cov.: 44 AF XY: 0.499 AC XY: 362906 AN XY: 726712

African (AFR) AF: 0.691 AC: 23105 AN: 33438

American (AMR) AF: 0.677 AC: 30220 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 13724 AN: 26108

East Asian (EAS) AF: 0.458 AC: 18170 AN: 39682

South Asian (SAS) AF: 0.747 AC: 64389 AN: 86240

European-Finnish (FIN) AF: 0.394 AC: 21038 AN: 53414

Middle Eastern (MID) AF: 0.553 AC: 3184 AN: 5762

European-Non Finnish (NFE) AF: 0.463 AC: 513971 AN: 1111122

Other (OTH) AF: 0.512 AC: 30864 AN: 60334

GnomAD4 genome AF: 0.549 AC: 83203 AN: 151644 Hom.: 23672 Cov.: 30 AF XY: 0.550 AC XY: 40714 AN XY: 74086

African (AFR) AF: 0.687 AC: 28415 AN: 41348

American (AMR) AF: 0.608 AC: 9257 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1770 AN: 3458

East Asian (EAS) AF: 0.478 AC: 2445 AN: 5116

South Asian (SAS) AF: 0.752 AC: 3612 AN: 4800

European-Finnish (FIN) AF: 0.387 AC: 4077 AN: 10530

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31884 AN: 67864

Other (OTH) AF: 0.555 AC: 1170 AN: 2110

Alfa AF: 0.502 Hom.: 38830

Bravo AF: 0.567

Asia WGS AF: 0.650 AC: 2260 AN: 3478

EpiCase AF: 0.479

EpiControl AF: 0.481

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Donnai-Barrow syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1
DANN	Benign	0.22
PhyloP100		0.42
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2241190;

hg19: chr2-170115588;

COSMIC: COSV55546459;