chr2-169143205-A-G

Position:

• chr2-169143205-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004525.3(LRP2):​c.12989-412T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 152,146 control chromosomes in the GnomAD database, including 40,061 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 0.72 (40061 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0560

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.12989-412T>C		intron_variant		ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.12860-412T>C		intron_variant			XP_011509485.1
LRP2	XM_011511184.3	c.10700-412T>C		intron_variant			XP_011509486.1
LRP2	XM_047444340.1	c.12065-412T>C		intron_variant			XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.12989-412T>C		intron_variant			NM_004525.3	ENSP00000496870	P1
LRP2	ENST00000649153.1	c.3889-412T>C		intron_variant, NMD_transcript_variant				ENSP00000497617
LRP2	ENST00000650252.1	c.*700-412T>C		intron_variant, NMD_transcript_variant				ENSP00000496887

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109667 AN: 152028 Hom.: 40041 Cov.: 32

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.750

Gnomad AMR AF: 0.757

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.857

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.730

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

GnomAD4 genome AF: 0.721 AC: 109739 AN: 152146 Hom.: 40061 Cov.: 32 AF XY: 0.721 AC XY: 53641 AN XY: 74388

Gnomad4 AFR AF: 0.636

Gnomad4 AMR AF: 0.757

Gnomad4 ASJ AF: 0.686

Gnomad4 EAS AF: 0.470

Gnomad4 SAS AF: 0.857

Gnomad4 FIN AF: 0.716

Gnomad4 NFE AF: 0.776

Gnomad4 OTH AF: 0.730

Alfa AF: 0.751 Hom.: 9108

Bravo AF: 0.717

Asia WGS AF: 0.679 AC: 2363 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.66
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs6733122; hg19: chr2-169999715;