rs830973

Positions:

• chr2-169239508-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004525.3(LRP2):​c.4294+19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 1,613,190 control chromosomes in the GnomAD database, including 98,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10353 hom., cov: 32)
  • Exomes 𝑓: 0.34 (88019 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.24

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=-0.84).
• BP6: Variant 2-169239508-G-A is Benign according to our data. Variant chr2-169239508-G-A is described in ClinVar as [Benign]. Clinvar id is 259418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169239508-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.4294+19C>T		intron_variant		ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.4294+19C>T		intron_variant			XP_011509485.1
LRP2	XM_047444340.1	c.3370+19C>T		intron_variant			XP_047300296.1
LRP2	XM_011511184.3	c.2005+19C>T		intron_variant			XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.4294+19C>T		intron_variant			NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55059 AN: 151804 Hom.: 10336 Cov.: 32

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.356

GnomAD3 exomes AF: 0.400 AC: 100412 AN: 251200 Hom.: 22035 AF XY: 0.400 AC XY: 54344 AN XY: 135800

Gnomad AFR exome AF: 0.394

Gnomad AMR exome AF: 0.583

Gnomad ASJ exome AF: 0.353

Gnomad EAS exome AF: 0.466

Gnomad SAS exome AF: 0.571

Gnomad FIN exome AF: 0.303

Gnomad NFE exome AF: 0.313

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.336 AC: 491461 AN: 1461268 Hom.: 88019 Cov.: 40 AF XY: 0.342 AC XY: 248876 AN XY: 726950

Gnomad4 AFR exome AF: 0.390

Gnomad4 AMR exome AF: 0.568

Gnomad4 ASJ exome AF: 0.348

Gnomad4 EAS exome AF: 0.445

Gnomad4 SAS exome AF: 0.567

Gnomad4 FIN exome AF: 0.304

Gnomad4 NFE exome AF: 0.304

Gnomad4 OTH exome AF: 0.350

GnomAD4 genome AF: 0.363 AC: 55102 AN: 151922 Hom.: 10353 Cov.: 32 AF XY: 0.368 AC XY: 27334 AN XY: 74244

Gnomad4 AFR AF: 0.390

Gnomad4 AMR AF: 0.455

Gnomad4 ASJ AF: 0.342

Gnomad4 EAS AF: 0.468

Gnomad4 SAS AF: 0.585

Gnomad4 FIN AF: 0.304

Gnomad4 NFE AF: 0.313

Gnomad4 OTH AF: 0.363

Alfa AF: 0.341 Hom.: 4958

Bravo AF: 0.373

Asia WGS AF: 0.527 AC: 1831 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Donnai-Barrow syndrome Benign:1

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	-0.84
CADD	Benign	8.3
DANN	Benign	0.37

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: rs830973; hg19: chr2-170096018; COSMIC: COSV55540257; COSMIC: COSV55540257;