2-169256524-G-T

Variant names:

• chr2-169256524-G-T
• rs830958
• NM_004525.3:c.2640-288C>A

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.2640-288C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.923 in 152,178 control chromosomes in the GnomAD database, including 64,978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.92 (64978 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.666
• Publications: 8 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Stickler syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 2-169256524-G-T is Benign according to our data. Variant chr2-169256524-G-T is described in ClinVar as Benign. ClinVar VariationId is 1246474.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.2640-288C>A		intron	N/A	NP_004516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.2640-288C>A		intron	N/A	ENSP00000496870.1
	LRP2	ENST00000443831.1	TSL:2	c.2229-288C>A		intron	N/A	ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.923 AC: 140296 AN: 152060 Hom.: 64919 Cov.: 32

Gnomad AFR AF: 0.979

Gnomad AMI AF: 0.859

Gnomad AMR AF: 0.928

Gnomad ASJ AF: 0.823

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.913

Gnomad FIN AF: 0.907

Gnomad MID AF: 0.901

Gnomad NFE AF: 0.891

Gnomad OTH AF: 0.909

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

GnomAD4 genome AF: 0.923 AC: 140412 AN: 152178 Hom.: 64978 Cov.: 32 AF XY: 0.924 AC XY: 68763 AN XY: 74406

African (AFR) AF: 0.979 AC: 40672 AN: 41540

American (AMR) AF: 0.928 AC: 14179 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 2855 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5165 AN: 5170

South Asian (SAS) AF: 0.913 AC: 4404 AN: 4826

European-Finnish (FIN) AF: 0.907 AC: 9609 AN: 10596

Middle Eastern (MID) AF: 0.901 AC: 263 AN: 292

European-Non Finnish (NFE) AF: 0.891 AC: 60562 AN: 67988

Other (OTH) AF: 0.909 AC: 1920 AN: 2112

Alfa AF: 0.896 Hom.: 52957

Bravo AF: 0.928

Asia WGS AF: 0.964 AC: 3344 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.21
DANN	Benign	0.56
PhyloP100		-0.67
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: rs830958; hg19: chr2-170113034;