2-169246826-T-C

Position:

• chr2-169246826-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004525.3(LRP2):​c.3069A>G​(p.Thr1023Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,613,722 control chromosomes in the GnomAD database, including 198,654 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23270 hom., cov: 32)
  • Exomes 𝑓: 0.48 (175384 hom.)
• Consequence: LRP2 NM_004525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.936

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-169246826-T-C is Benign according to our data. Variant chr2-169246826-T-C is described in ClinVar as [Benign]. Clinvar id is 129516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169246826-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.936 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.3069A>G	p.Thr1023Thr	synonymous_variant	21/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.3069A>G	p.Thr1023Thr	synonymous_variant	21/78		XP_011509485.1
LRP2	XM_047444340.1	c.2145A>G	p.Thr715Thr	synonymous_variant	21/79		XP_047300296.1
LRP2	XM_011511184.3	c.780A>G	p.Thr260Thr	synonymous_variant	6/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.3069A>G	p.Thr1023Thr	synonymous_variant	21/79		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.2658A>G	p.Thr886Thr	synonymous_variant	19/23	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82313 AN: 151868 Hom.: 23236 Cov.: 32

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.540

GnomAD3 exomes AF: 0.538 AC: 135235 AN: 251424 Hom.: 38494 AF XY: 0.540 AC XY: 73348 AN XY: 135876

Gnomad AFR exome AF: 0.697

Gnomad AMR exome AF: 0.673

Gnomad ASJ exome AF: 0.542

Gnomad EAS exome AF: 0.476

Gnomad SAS exome AF: 0.747

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.458

Gnomad OTH exome AF: 0.497

GnomAD4 exome AF: 0.481 AC: 703444 AN: 1461736 Hom.: 175384 Cov.: 66 AF XY: 0.489 AC XY: 355339 AN XY: 727192

Gnomad4 AFR exome AF: 0.695

Gnomad4 AMR exome AF: 0.663

Gnomad4 ASJ exome AF: 0.524

Gnomad4 EAS exome AF: 0.457

Gnomad4 SAS exome AF: 0.741

Gnomad4 FIN exome AF: 0.388

Gnomad4 NFE exome AF: 0.450

Gnomad4 OTH exome AF: 0.501

GnomAD4 genome AF: 0.542 AC: 82403 AN: 151986 Hom.: 23270 Cov.: 32 AF XY: 0.544 AC XY: 40376 AN XY: 74278

Gnomad4 AFR AF: 0.690

Gnomad4 AMR AF: 0.597

Gnomad4 ASJ AF: 0.511

Gnomad4 EAS AF: 0.477

Gnomad4 SAS AF: 0.748

Gnomad4 FIN AF: 0.383

Gnomad4 NFE AF: 0.457

Gnomad4 OTH AF: 0.545

Alfa AF: 0.480 Hom.: 35590

Bravo AF: 0.560

Asia WGS AF: 0.650 AC: 2259 AN: 3478

EpiCase AF: 0.468

EpiControl AF: 0.469

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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	Aug 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.36
DANN	Benign	0.28

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs831043; hg19: chr2-170103336; COSMIC: COSV55546447;