2-169334455-T-C

Variant names:

• chr2-169334455-T-C
• rs6433115
• NM_004525.3:c.80-13571A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004525.3(LRP2):​c.80-13571A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 152,100 control chromosomes in the GnomAD database, including 3,713 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (3713 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0110
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.80-13571A>G		intron_variant	Intron 1 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.80-13571A>G		intron_variant	Intron 1 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.-846+8080A>G		intron_variant	Intron 1 of 78		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.80-13571A>G		intron_variant	Intron 1 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.80-13571A>G		intron_variant	Intron 1 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33013 AN: 151982 Hom.: 3709 Cov.: 32

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.216

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.217 AC: 33029 AN: 152100 Hom.: 3713 Cov.: 32 AF XY: 0.218 AC XY: 16183 AN XY: 74356

African (AFR) AF: 0.265 AC: 11002 AN: 41466

American (AMR) AF: 0.158 AC: 2423 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 678 AN: 3470

East Asian (EAS) AF: 0.276 AC: 1428 AN: 5168

South Asian (SAS) AF: 0.146 AC: 705 AN: 4828

European-Finnish (FIN) AF: 0.194 AC: 2056 AN: 10574

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14040 AN: 67984

Other (OTH) AF: 0.214 AC: 452 AN: 2116

Alfa AF: 0.186 Hom.: 1472

Bravo AF: 0.216

Asia WGS AF: 0.183 AC: 636 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.3
DANN	Benign	0.53
PhyloP100		0.011
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs6433115; hg19: chr2-170190965;