rs831003

Variant names:

• chr2-169277681-G-C
• rs831003
• NM_004525.3:c.1772+64C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-169277681-G-C
• chr2-169277681-G-A
• chr2-169277681-G-T

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.1772+64C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.775 in 1,405,144 control chromosomes in the GnomAD database, including 423,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45681 hom., cov: 32)
  • Exomes 𝑓: 0.77 (378091 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.518
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-169277681-G-C is Benign according to our data. Variant chr2-169277681-G-C is described in ClinVar as Benign. ClinVar VariationId is 1295179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.893 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.1772+64C>G		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.1772+64C>G		intron	N/A	ENSP00000496870.1	P98164
	LRP2	ENST00000443831.1	TSL:2	c.1565+1691C>G		intron	N/A	ENSP00000409813.1	E9PC35

Frequencies

GnomAD3 genomes AF: 0.774 AC: 117620 AN: 151982 Hom.: 45641 Cov.: 32

Gnomad AFR AF: 0.742

Gnomad AMI AF: 0.800

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.824

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.607

Gnomad FIN AF: 0.806

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.803

GnomAD4 exome AF: 0.775 AC: 970618 AN: 1253042 Hom.: 378091 AF XY: 0.769 AC XY: 487316 AN XY: 633902

African (AFR) AF: 0.745 AC: 21655 AN: 29060

American (AMR) AF: 0.797 AC: 34718 AN: 43584

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 20470 AN: 24818

East Asian (EAS) AF: 0.899 AC: 34483 AN: 38350

South Asian (SAS) AF: 0.606 AC: 49115 AN: 81088

European-Finnish (FIN) AF: 0.808 AC: 42870 AN: 53064

Middle Eastern (MID) AF: 0.816 AC: 4378 AN: 5366

European-Non Finnish (NFE) AF: 0.781 AC: 721466 AN: 924314

Other (OTH) AF: 0.776 AC: 41463 AN: 53398

GnomAD4 genome AF: 0.774 AC: 117717 AN: 152102 Hom.: 45681 Cov.: 32 AF XY: 0.773 AC XY: 57450 AN XY: 74356

African (AFR) AF: 0.742 AC: 30776 AN: 41466

American (AMR) AF: 0.795 AC: 12145 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 2859 AN: 3470

East Asian (EAS) AF: 0.915 AC: 4738 AN: 5178

South Asian (SAS) AF: 0.606 AC: 2923 AN: 4820

European-Finnish (FIN) AF: 0.806 AC: 8529 AN: 10588

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.781 AC: 53088 AN: 67988

Other (OTH) AF: 0.799 AC: 1683 AN: 2106

Alfa AF: 0.777 Hom.: 5725

Bravo AF: 0.778

Asia WGS AF: 0.738 AC: 2569 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.47
PhyloP100		-0.52
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: rs831003; hg19: chr2-170134191;