2-169177485-T-C

Variant names:

• chr2-169177485-T-C
• rs7565788
• NM_004525.3:c.10393+318A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004525.3(LRP2):​c.10393+318A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 151,968 control chromosomes in the GnomAD database, including 43,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.75 (43217 hom., cov: 31)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.752
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-169177485-T-C is Benign according to our data. Variant chr2-169177485-T-C is described in ClinVar as Benign. ClinVar VariationId is 1279171.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.833 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.10393+318A>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.10393+318A>G		intron	N/A	ENSP00000496870.1	P98164
	LRP2	ENST00000649153.1		n.1291+318A>G		intron	N/A	ENSP00000497617.1	A0A3B3IT64

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114254 AN: 151852 Hom.: 43180 Cov.: 31

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.721

Gnomad AMR AF: 0.787

Gnomad ASJ AF: 0.740

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.759

Gnomad OTH AF: 0.766

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

GnomAD4 genome AF: 0.752 AC: 114352 AN: 151968 Hom.: 43217 Cov.: 31 AF XY: 0.752 AC XY: 55828 AN XY: 74288

African (AFR) AF: 0.759 AC: 31478 AN: 41450

American (AMR) AF: 0.787 AC: 12015 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.740 AC: 2566 AN: 3468

East Asian (EAS) AF: 0.501 AC: 2596 AN: 5178

South Asian (SAS) AF: 0.855 AC: 4119 AN: 4820

European-Finnish (FIN) AF: 0.714 AC: 7515 AN: 10520

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.759 AC: 51542 AN: 67950

Other (OTH) AF: 0.768 AC: 1620 AN: 2110

Alfa AF: 0.762 Hom.: 22022

Bravo AF: 0.752

Asia WGS AF: 0.712 AC: 2474 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.30
DANN	Benign	0.41
PhyloP100		-0.75
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: rs7565788; hg19: chr2-170033995;