Variant chr2-169127556-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004525.3(LRP2):c.*1107G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0035 ( 4 hom., cov: 19)

Exomes 𝑓: 0.029 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LRP2
NM_004525.3 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.28

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.*1107G>T	3_prime_UTR_variant	79/79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.*1107G>T	3_prime_UTR_variant	78/78		XP_011509485.1
LRP2	XM_047444340.1 link	c.*1107G>T	3_prime_UTR_variant	79/79		XP_047300296.1
LRP2	XM_011511184.3 link	c.*1107G>T	3_prime_UTR_variant	64/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046 link	c.*1107G>T		3_prime_UTR_variant	79/79		NM_004525.3	ENSP00000496870.1		P98164

Frequencies

GnomAD3 genomes

AF:

0.00353

AC:

238

AN:

67368

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000356

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000809

Gnomad ASJ

AF:

0.00111

Gnomad EAS

AF:

0.0684

Gnomad SAS

AF:

0.000986

Gnomad FIN

AF:

0.00284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000226

Gnomad OTH

AF:

0.00318

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0286

AC:

AN:

210

Hom.:

Cov.:

AF XY:

0.0211

AC XY:

AN XY:

142

show subpopulations

Gnomad4 EAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0417

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00355

AC:

239

AN:

67368

Hom.:

Cov.:

AF XY:

0.00401

AC XY:

129

AN XY:

32186

show subpopulations

Gnomad4 AFR

AF:

0.000355

Gnomad4 AMR

AF:

0.000809

Gnomad4 ASJ

AF:

0.00111

Gnomad4 EAS

AF:

0.0684

Gnomad4 SAS

AF:

0.000993

Gnomad4 FIN

AF:

0.00284

Gnomad4 NFE

AF:

0.000226

Gnomad4 OTH

AF:

0.00524

Alfa

AF:

0.000843

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Donnai-Barrow syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.45

DANN

Benign

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over