2-169128119-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004525.3(LRP2):c.*544T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 160,814 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.050 (196 hom., cov: 32)
  • Exomes 𝑓: 0.048 (16 hom.)
• Consequence: LRP2 NM_004525.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.52

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-169128119-A-G is Benign according to our data. Variant chr2-169128119-A-G is described in ClinVar as [Benign]. Clinvar id is 332058.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.*544T>C		3_prime_UTR_variant	79/79	ENST00000649046.1
LRP2	XM_011511183.4	c.*544T>C		3_prime_UTR_variant	78/78
LRP2	XM_011511184.3	c.*544T>C		3_prime_UTR_variant	64/64
LRP2	XM_047444340.1	c.*544T>C		3_prime_UTR_variant	79/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.*544T>C		3_prime_UTR_variant	79/79		NM_004525.3	P1
LRP2	ENST00000650252.1	c.*2186T>C		3_prime_UTR_variant, NMD_transcript_variant	24/24

Frequencies

GnomAD3 genomes AF: 0.0502 AC: 7644 AN: 152184 Hom.: 194 Cov.: 32

Gnomad AFR AF: 0.0578

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00750

Gnomad SAS AF: 0.0605

Gnomad FIN AF: 0.0455

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0555

Gnomad OTH AF: 0.0440

GnomAD4 exome AF: 0.0482 AC: 410 AN: 8512 Hom.: 16 Cov.: 0 AF XY: 0.0499 AC XY: 240 AN XY: 4806

Gnomad4 AFR exome AF: 0.0682

Gnomad4 AMR exome AF: 0.0173

Gnomad4 ASJ exome AF: 0.0208

Gnomad4 EAS exome AF: 0.0138

Gnomad4 SAS exome AF: 0.0617

Gnomad4 FIN exome AF: 0.0607

Gnomad4 NFE exome AF: 0.0517

Gnomad4 OTH exome AF: 0.0621

GnomAD4 genome AF: 0.0503 AC: 7663 AN: 152302 Hom.: 196 Cov.: 32 AF XY: 0.0486 AC XY: 3623 AN XY: 74474

Gnomad4 AFR AF: 0.0580

Gnomad4 AMR AF: 0.0268

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.00752

Gnomad4 SAS AF: 0.0612

Gnomad4 FIN AF: 0.0455

Gnomad4 NFE AF: 0.0555

Gnomad4 OTH AF: 0.0445

Alfa AF: 0.0518 Hom.: 44

Bravo AF: 0.0491

Asia WGS AF: 0.0330 AC: 113 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Donnai-Barrow syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.10
Dann	Benign	0.53

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: rs79052831; hg19: chr2-169984629;