rs830995

Variant names:

• chr2-169273126-A-G
• rs830995
• NM_004525.3:c.1976-59T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-169273126-A-G
• chr2-169273126-A-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.1976-59T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 1,600,436 control chromosomes in the GnomAD database, including 398,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36325 hom., cov: 31)
  • Exomes 𝑓: 0.70 (362492 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.16
• Publications: 12 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=-0.83).
• BP6: Variant 2-169273126-A-G is Benign according to our data. Variant chr2-169273126-A-G is described in ClinVar as Benign. ClinVar VariationId is 1232462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.886 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.1976-59T>C		intron_variant	Intron 14 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.1976-59T>C		intron_variant	Intron 14 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.1052-59T>C		intron_variant	Intron 14 of 78		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.1976-59T>C		intron_variant	Intron 14 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.1769-59T>C		intron_variant	Intron 13 of 22	2		ENSP00000409813.1
LRP2	ENST00000493501.1	n.319-59T>C		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes AF: 0.688 AC: 104494 AN: 151946 Hom.: 36312 Cov.: 31

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.739

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.760

Gnomad EAS AF: 0.907

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.720

GnomAD4 exome AF: 0.704 AC: 1020264 AN: 1448372 Hom.: 362492 AF XY: 0.701 AC XY: 505855 AN XY: 721500

African (AFR) AF: 0.648 AC: 21506 AN: 33196

American (AMR) AF: 0.527 AC: 23461 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 19879 AN: 25980

East Asian (EAS) AF: 0.873 AC: 34592 AN: 39604

South Asian (SAS) AF: 0.559 AC: 48021 AN: 85940

European-Finnish (FIN) AF: 0.742 AC: 38773 AN: 52284

Middle Eastern (MID) AF: 0.749 AC: 4288 AN: 5728

European-Non Finnish (NFE) AF: 0.715 AC: 787315 AN: 1101206

Other (OTH) AF: 0.708 AC: 42429 AN: 59900

GnomAD4 genome AF: 0.688 AC: 104549 AN: 152064 Hom.: 36325 Cov.: 31 AF XY: 0.684 AC XY: 50876 AN XY: 74338

African (AFR) AF: 0.643 AC: 26683 AN: 41486

American (AMR) AF: 0.591 AC: 9028 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.760 AC: 2636 AN: 3470

East Asian (EAS) AF: 0.908 AC: 4676 AN: 5152

South Asian (SAS) AF: 0.559 AC: 2695 AN: 4822

European-Finnish (FIN) AF: 0.739 AC: 7826 AN: 10586

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.715 AC: 48602 AN: 67958

Other (OTH) AF: 0.717 AC: 1518 AN: 2116

Alfa AF: 0.697 Hom.: 18301

Bravo AF: 0.682

Asia WGS AF: 0.697 AC: 2425 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.7
DANN	Benign	0.55
PhyloP100		2.2
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: rs830995; hg19: chr2-170129636;