rs830973

Variant names:

• chr2-169239508-G-A
• rs830973
• NM_004525.3:c.4294+19C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 publications found

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]

LRP2 Gene-Disease associations (from GenCC):

• Donnai-Barrow syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Stickler syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 259418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.4294+19C>T		intron	N/A	NP_004516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.4294+19C>T		intron	N/A	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

GnomAD2 exomes AF: 0.400 AC: 100412 AN: 251200 AF XY: 0.400

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 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

African (AFR) AF: 0.390 AC: 13044 AN: 33464

American (AMR) AF: 0.568 AC: 25396 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 9084 AN: 26124

East Asian (EAS) AF: 0.445 AC: 17642 AN: 39686

South Asian (SAS) AF: 0.567 AC: 48914 AN: 86226

European-Finnish (FIN) AF: 0.304 AC: 16245 AN: 53406

Middle Eastern (MID) AF: 0.374 AC: 2158 AN: 5766

European-Non Finnish (NFE) AF: 0.304 AC: 337855 AN: 1111506

Other (OTH) AF: 0.350 AC: 21123 AN: 60378

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

African (AFR) AF: 0.390 AC: 16157 AN: 41424

American (AMR) AF: 0.455 AC: 6944 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1184 AN: 3464

East Asian (EAS) AF: 0.468 AC: 2415 AN: 5164

South Asian (SAS) AF: 0.585 AC: 2817 AN: 4812

European-Finnish (FIN) AF: 0.304 AC: 3206 AN: 10546

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21259 AN: 67956

Other (OTH) AF: 0.363 AC: 766 AN: 2110

Alfa AF: 0.339 Hom.: 5398

Bravo AF: 0.373

Asia WGS AF: 0.527 AC: 1831 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Donnai-Barrow syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.3
DANN	Benign	0.37
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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