rs76714416

Variant names:

• chr2-169239781-A-G
• rs76714416
• NM_004525.3:c.4046-6T>C

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.4046-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,612,340 control chromosomes in the GnomAD database, including 761 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (353 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (408 hom.)
• Consequence: LRP2 NM_004525.3 splice_region, intron
• Scores: Splicing: ADA: 0.00009669
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.77
• Publications: 4 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=-0.79).
• BP6: Variant 2-169239781-A-G is Benign according to our data. Variant chr2-169239781-A-G is described in ClinVar as Benign. ClinVar VariationId is 129522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.4046-6T>C		splice_region intron	N/A	NP_004516.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.4046-6T>C		splice_region intron	N/A	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6295 AN: 152168 Hom.: 349 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.00444

Gnomad OTH AF: 0.0444

GnomAD2 exomes AF: 0.0167 AC: 4167 AN: 250248 AF XY: 0.0148

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.00964

Gnomad ASJ exome AF: 0.0362

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00580

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.00900 AC: 13146 AN: 1460054 Hom.: 408 Cov.: 32 AF XY: 0.00927 AC XY: 6736 AN XY: 726484

African (AFR) AF: 0.136 AC: 4556 AN: 33400

American (AMR) AF: 0.0110 AC: 492 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0342 AC: 894 AN: 26112

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39672

South Asian (SAS) AF: 0.0201 AC: 1732 AN: 86210

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53380

Middle Eastern (MID) AF: 0.0420 AC: 242 AN: 5768

European-Non Finnish (NFE) AF: 0.00376 AC: 4176 AN: 1110460

Other (OTH) AF: 0.0172 AC: 1039 AN: 60332

GnomAD4 genome AF: 0.0415 AC: 6322 AN: 152286 Hom.: 353 Cov.: 32 AF XY: 0.0402 AC XY: 2992 AN XY: 74478

African (AFR) AF: 0.130 AC: 5396 AN: 41548

American (AMR) AF: 0.0188 AC: 288 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.00443 AC: 301 AN: 68016

Other (OTH) AF: 0.0440 AC: 93 AN: 2116

Alfa AF: 0.0234 Hom.: 102

Bravo AF: 0.0463

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00984

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Donnai-Barrow syndrome (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	10
DANN	Benign	0.59
PhyloP100		1.8
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000097
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.090		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: rs76714416; hg19: chr2-170096291; COSMIC: COSV55558501;