rs990626

Variant names:

• chr2-169140541-G-A
• rs990626
• NM_004525.3:c.13113C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-169140541-G-A
• chr2-169140541-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004525.3(LRP2):​c.13113C>T​(p.Ile4371Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 1,610,642 control chromosomes in the GnomAD database, including 424,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I4371I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.61 (30943 hom., cov: 32)
  • Exomes 𝑓: 0.73 (393280 hom.)
• Consequence: LRP2 NM_004525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.51
• Publications: 33 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-169140541-G-A is Benign according to our data. Variant chr2-169140541-G-A is described in ClinVar as Benign. ClinVar VariationId is 129502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.758 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.13113C>T	p.Ile4371Ile	synonymous	Exon 72 of 79	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.13113C>T	p.Ile4371Ile	synonymous	Exon 72 of 79	ENSP00000496870.1	P98164
	LRP2	ENST00000649153.1		n.4007-931C>T		intron	N/A	ENSP00000497617.1	A0A3B3IT64
	LRP2	ENST00000650252.1		n.*820-33C>T		intron	N/A	ENSP00000496887.1	A0A3B3IRR0

Frequencies

GnomAD3 genomes AF: 0.609 AC: 92431 AN: 151894 Hom.: 30938 Cov.: 32

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.751

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.633

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.779

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.749

Gnomad OTH AF: 0.631

GnomAD2 exomes AF: 0.691 AC: 173322 AN: 250652 AF XY: 0.704

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.652

Gnomad EAS exome AF: 0.465

Gnomad FIN exome AF: 0.716

Gnomad NFE exome AF: 0.746

Gnomad OTH exome AF: 0.708

GnomAD4 exome AF: 0.728 AC: 1062528 AN: 1458630 Hom.: 393280 Cov.: 37 AF XY: 0.731 AC XY: 530522 AN XY: 725800

African (AFR) AF: 0.298 AC: 9952 AN: 33406

American (AMR) AF: 0.730 AC: 32636 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 17068 AN: 26120

East Asian (EAS) AF: 0.428 AC: 16989 AN: 39672

South Asian (SAS) AF: 0.773 AC: 66617 AN: 86168

European-Finnish (FIN) AF: 0.715 AC: 38050 AN: 53254

Middle Eastern (MID) AF: 0.724 AC: 4168 AN: 5758

European-Non Finnish (NFE) AF: 0.753 AC: 835184 AN: 1109276

Other (OTH) AF: 0.694 AC: 41864 AN: 60284

GnomAD4 genome AF: 0.608 AC: 92444 AN: 152012 Hom.: 30943 Cov.: 32 AF XY: 0.610 AC XY: 45323 AN XY: 74304

African (AFR) AF: 0.316 AC: 13089 AN: 41448

American (AMR) AF: 0.681 AC: 10407 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 2199 AN: 3472

East Asian (EAS) AF: 0.462 AC: 2381 AN: 5158

South Asian (SAS) AF: 0.779 AC: 3747 AN: 4812

European-Finnish (FIN) AF: 0.708 AC: 7476 AN: 10566

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.749 AC: 50915 AN: 67968

Other (OTH) AF: 0.631 AC: 1333 AN: 2112

Alfa AF: 0.697 Hom.: 147671

Bravo AF: 0.588

Asia WGS AF: 0.613 AC: 2130 AN: 3478

EpiCase AF: 0.750

EpiControl AF: 0.749

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Donnai-Barrow syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.9
DANN	Benign	0.65
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -33

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs990626; hg19: chr2-169997051; COSMIC: COSV55577544; COSMIC: COSV55577544;