2-169152968-C-T

Position:

• chr2-169152968-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004525.3(LRP2):​c.12296-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000471 in 1,613,540 control chromosomes in the GnomAD database, including 10 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (10 hom.)
• Consequence: LRP2 NM_004525.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002023
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.0630

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-169152968-C-T is Benign according to our data. Variant chr2-169152968-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211389.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr2-169152968-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000269 (41/152244) while in subpopulation SAS AF= 0.00581 (28/4818). AF 95% confidence interval is 0.00413. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.12296-4G>A		splice_region_variant, intron_variant		ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.12167-4G>A		splice_region_variant, intron_variant			XP_011509485.1
LRP2	XM_047444340.1	c.11372-4G>A		splice_region_variant, intron_variant			XP_047300296.1
LRP2	XM_011511184.3	c.10007-4G>A		splice_region_variant, intron_variant			XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.12296-4G>A		splice_region_variant, intron_variant			NM_004525.3	ENSP00000496870.1
LRP2	ENST00000649153.1	n.3194-4G>A		splice_region_variant, intron_variant				ENSP00000497617.1
LRP2	ENST00000650252.1	n.*7-4G>A		splice_region_variant, intron_variant				ENSP00000496887.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00107 AC: 269 AN: 251220 Hom.: 6 AF XY: 0.00137 AC XY: 186 AN XY: 135768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00777

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000492 AC: 719 AN: 1461296 Hom.: 10 Cov.: 31 AF XY: 0.000693 AC XY: 504 AN XY: 726966

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00685

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74448

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00581

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000121

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Donnai-Barrow syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	LRP2: BP4, BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 10, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.0
DANN	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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: rs375166826; hg19: chr2-170009478;