2-169168688-GAA-GA

Position:

• chr2-169168688-GAA-GA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004525.3(LRP2):​c.11498-13del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0936 in 1,613,584 control chromosomes in the GnomAD database, including 7,947 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (530 hom., cov: 29)
  • Exomes 𝑓: 0.096 (7417 hom.)
• Consequence: LRP2 NM_004525.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.78

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 -16 ACMG points.

• BP6: Variant 2-169168688-GA-G is Benign according to our data. Variant chr2-169168688-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 259412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169168688-GA-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.11498-13del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.11369-13del		splice_polypyrimidine_tract_variant, intron_variant			XP_011509485.1
LRP2	XM_011511184.3	c.9209-13del		splice_polypyrimidine_tract_variant, intron_variant			XP_011509486.1
LRP2	XM_047444340.1	c.10574-13del		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.11498-13del		splice_polypyrimidine_tract_variant, intron_variant			NM_004525.3	ENSP00000496870	P1
LRP2	ENST00000649153.1	c.2398-13del		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant				ENSP00000497617
LRP2	ENST00000650252.1	c.530-13del		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant				ENSP00000496887

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10903 AN: 152078 Hom.: 529 Cov.: 29

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0530

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.0905

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0636

GnomAD3 exomes AF: 0.0763 AC: 19145 AN: 250854 Hom.: 898 AF XY: 0.0777 AC XY: 10540 AN XY: 135588

Gnomad AFR exome AF: 0.0212

Gnomad AMR exome AF: 0.0357

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.00687

Gnomad SAS exome AF: 0.0503

Gnomad FIN exome AF: 0.0908

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.0880

GnomAD4 exome AF: 0.0958 AC: 140067 AN: 1461388 Hom.: 7417 Cov.: 31 AF XY: 0.0951 AC XY: 69153 AN XY: 727032

Gnomad4 AFR exome AF: 0.0179

Gnomad4 AMR exome AF: 0.0374

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.00867

Gnomad4 SAS exome AF: 0.0518

Gnomad4 FIN exome AF: 0.0900

Gnomad4 NFE exome AF: 0.106

Gnomad4 OTH exome AF: 0.0927

GnomAD4 genome AF: 0.0716 AC: 10903 AN: 152196 Hom.: 530 Cov.: 29 AF XY: 0.0696 AC XY: 5181 AN XY: 74400

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.0529

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.00850

Gnomad4 SAS AF: 0.0515

Gnomad4 FIN AF: 0.0905

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.0649

Bravo AF: 0.0666

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Donnai-Barrow syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs143342962; hg19: chr2-170025198;