rs3944004

Variant names:

• chr2-169151712-A-C
• rs3944004
• NM_004525.3:c.12462-686T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-169151712-A-C
• chr2-169151712-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004525.3(LRP2):​c.12462-686T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 152,088 control chromosomes in the GnomAD database, including 4,702 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (4702 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.849
• Publications: 6 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, Orphanet, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.356 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.12462-686T>G		intron	N/A	NP_004516.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.12462-686T>G		intron	N/A	ENSP00000496870.1
	LRP2	ENST00000649153.1		n.3360-686T>G		intron	N/A	ENSP00000497617.1
	LRP2	ENST00000650252.1		n.*173-686T>G		intron	N/A	ENSP00000496887.1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37064 AN: 151968 Hom.: 4698 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.262

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

GnomAD4 genome AF: 0.244 AC: 37092 AN: 152088 Hom.: 4702 Cov.: 32 AF XY: 0.245 AC XY: 18205 AN XY: 74324

African (AFR) AF: 0.275 AC: 11427 AN: 41484

American (AMR) AF: 0.166 AC: 2531 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 952 AN: 3472

East Asian (EAS) AF: 0.369 AC: 1909 AN: 5168

South Asian (SAS) AF: 0.359 AC: 1724 AN: 4802

European-Finnish (FIN) AF: 0.231 AC: 2441 AN: 10556

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.224 AC: 15247 AN: 68002

Other (OTH) AF: 0.263 AC: 556 AN: 2114

Alfa AF: 0.139 Hom.: 256

Bravo AF: 0.237

Asia WGS AF: 0.335 AC: 1163 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.89
PhyloP100		0.85
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: rs3944004; hg19: chr2-170008222;