2-169280527-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004525.3(LRP2):c.1172-8G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,613,612 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (10 hom., cov: 32)
  • Exomes 𝑓: 0.013 (132 hom.)
• Consequence: LRP2 NM_004525.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002768
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0480

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=-0.91).
• BP6: Variant 2-169280527-C-T is Benign according to our data. Variant chr2-169280527-C-T is described in ClinVar as [Benign]. Clinvar id is 129495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169280527-C-T is described in Lovd as [Likely_benign]. Variant chr2-169280527-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00937 (1427/152224) while in subpopulation AMR AF= 0.0148 (226/15282). AF 95% confidence interval is 0.0133. There are 10 homozygotes in gnomad4. There are 659 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.1172-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000649046.1
LRP2	XM_011511183.4	c.1172-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
LRP2	XM_047444340.1	c.248-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.1172-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_004525.3	P1
LRP2	ENST00000443831.1	c.1172-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00939 AC: 1428 AN: 152106 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00929 AC: 2325 AN: 250264 Hom.: 16 AF XY: 0.00956 AC XY: 1293 AN XY: 135294

Gnomad AFR exome AF: 0.00266

Gnomad AMR exome AF: 0.00838

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00197

Gnomad FIN exome AF: 0.00367

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.0125 AC: 18325 AN: 1461388 Hom.: 132 Cov.: 31 AF XY: 0.0123 AC XY: 8966 AN XY: 726970

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.00882

Gnomad4 ASJ exome AF: 0.0115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00198

Gnomad4 FIN exome AF: 0.00382

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.0115

GnomAD4 genome AF: 0.00937 AC: 1427 AN: 152224 Hom.: 10 Cov.: 32 AF XY: 0.00885 AC XY: 659 AN XY: 74426

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.0120 Hom.: 3

Bravo AF: 0.00950

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Donnai-Barrow syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	LRP2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	2.2
Dann	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.0080
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: rs115371758; hg19: chr2-170137037; COSMIC: COSV55569736;