rs2075254

Variant names:

• chr2-169243389-G-A
• rs2075254
• NM_004525.3:c.3550+14C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-169243389-G-A
• chr2-169243389-G-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.3550+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,610,778 control chromosomes in the GnomAD database, including 198,121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23015 hom., cov: 31)
  • Exomes 𝑓: 0.48 (175106 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.01
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Stickler syndrome

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

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• congenital heart disease

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-169243389-G-A is Benign according to our data. Variant chr2-169243389-G-A is described in ClinVar as Benign. ClinVar VariationId is 259413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.727 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.3550+14C>T		intron	N/A	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.3550+14C>T		intron	N/A	ENSP00000496870.1	P98164
	LRP2	ENST00000443831.1	TSL:2	c.3139+14C>T		intron	N/A	ENSP00000409813.1	E9PC35

Frequencies

GnomAD3 genomes AF: 0.541 AC: 81802 AN: 151314 Hom.: 22980 Cov.: 31

Gnomad AFR AF: 0.689

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.538

GnomAD2 exomes AF: 0.537 AC: 134748 AN: 251022 AF XY: 0.539

Gnomad AFR exome AF: 0.697

Gnomad AMR exome AF: 0.672

Gnomad ASJ exome AF: 0.542

Gnomad EAS exome AF: 0.473

Gnomad FIN exome AF: 0.385

Gnomad NFE exome AF: 0.457

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.481 AC: 701907 AN: 1459344 Hom.: 175106 Cov.: 37 AF XY: 0.488 AC XY: 354563 AN XY: 726030

African (AFR) AF: 0.695 AC: 23226 AN: 33434

American (AMR) AF: 0.663 AC: 29637 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 13680 AN: 26110

East Asian (EAS) AF: 0.456 AC: 18097 AN: 39680

South Asian (SAS) AF: 0.741 AC: 63853 AN: 86204

European-Finnish (FIN) AF: 0.387 AC: 20663 AN: 53378

Middle Eastern (MID) AF: 0.542 AC: 3124 AN: 5760

European-Non Finnish (NFE) AF: 0.450 AC: 499429 AN: 1109762

Other (OTH) AF: 0.501 AC: 30198 AN: 60316

GnomAD4 genome AF: 0.541 AC: 81894 AN: 151434 Hom.: 23015 Cov.: 31 AF XY: 0.542 AC XY: 40130 AN XY: 73976

African (AFR) AF: 0.689 AC: 28427 AN: 41260

American (AMR) AF: 0.596 AC: 9059 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1765 AN: 3462

East Asian (EAS) AF: 0.474 AC: 2432 AN: 5136

South Asian (SAS) AF: 0.748 AC: 3593 AN: 4806

European-Finnish (FIN) AF: 0.381 AC: 3985 AN: 10464

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30918 AN: 67794

Other (OTH) AF: 0.543 AC: 1146 AN: 2112

Alfa AF: 0.512 Hom.: 4601

Bravo AF: 0.560

Asia WGS AF: 0.647 AC: 2251 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.9
DANN	Benign	0.39
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2075254; hg19: chr2-170099899;