2-169162605-A-C

Position:

• chr2-169162605-A-C

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.11759-5T>G variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00256 in 1,614,108 control chromosomes in the GnomAD database, including 86 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 0.014 (47 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (39 hom.)
• Consequence: LRP2 NM_004525.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.5201
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.68

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=-0.8).
• BP6: Variant 2-169162605-A-C is Benign according to our data. Variant chr2-169162605-A-C is described in ClinVar as [Benign]. Clinvar id is 129496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2149/152358) while in subpopulation AFR AF= 0.048 (1994/41572). AF 95% confidence interval is 0.0462. There are 47 homozygotes in gnomad4. There are 997 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.11759-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.11630-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011509485.1
LRP2	XM_011511184.3	c.9470-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011509486.1
LRP2	XM_047444340.1	c.10835-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.11759-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_004525.3	ENSP00000496870	P1
LRP2	ENST00000649153.1	c.2659-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant				ENSP00000497617
LRP2	ENST00000650252.1	c.791-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant				ENSP00000496887

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2140 AN: 152240 Hom.: 47 Cov.: 33

Gnomad AFR AF: 0.0479

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00377 AC: 948 AN: 251196 Hom.: 15 AF XY: 0.00289 AC XY: 392 AN XY: 135746

Gnomad AFR exome AF: 0.0501

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00136 AC: 1983 AN: 1461750 Hom.: 39 Cov.: 32 AF XY: 0.00117 AC XY: 850 AN XY: 727178

Gnomad4 AFR exome AF: 0.0462

Gnomad4 AMR exome AF: 0.00376

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.0141 AC: 2149 AN: 152358 Hom.: 47 Cov.: 33 AF XY: 0.0134 AC XY: 997 AN XY: 74514

Gnomad4 AFR AF: 0.0480

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00142 Hom.: 3

Bravo AF: 0.0162

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -

Donnai-Barrow syndrome Benign:2

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

not specified Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	14
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.52
dbscSNV1_RF	Benign	0.46
SpliceAI score (max)		0.16		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: rs76488092; hg19: chr2-170019115; COSMIC: COSV104379204;