2-169277681-G-C

Position:

• chr2-169277681-G-C

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.1772+64C>G		intron_variant		ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.1772+64C>G		intron_variant			XP_011509485.1
LRP2	XM_047444340.1	c.848+64C>G		intron_variant			XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.1772+64C>G		intron_variant			NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.1565+1691C>G		intron_variant		2		ENSP00000409813.1

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

Gnomad4 AFR exome AF: 0.745

Gnomad4 AMR exome AF: 0.797

Gnomad4 ASJ exome AF: 0.825

Gnomad4 EAS exome AF: 0.899

Gnomad4 SAS exome AF: 0.606

Gnomad4 FIN exome AF: 0.808

Gnomad4 NFE exome AF: 0.781

Gnomad4 OTH exome AF: 0.776

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

Gnomad4 AFR AF: 0.742

Gnomad4 AMR AF: 0.795

Gnomad4 ASJ AF: 0.824

Gnomad4 EAS AF: 0.915

Gnomad4 SAS AF: 0.606

Gnomad4 FIN AF: 0.806

Gnomad4 NFE AF: 0.781

Gnomad4 OTH AF: 0.799

Alfa AF: 0.777 Hom.: 5725

Bravo AF: 0.778

Asia WGS AF: 0.738 AC: 2569 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.47

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: rs831003; hg19: chr2-170134191;