Genetic Variant NM_004525.3:c.12280A>C (chr2-169154475-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004525.3(LRP2):c.12280A>C(p.Lys4094Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K4094E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Failed GnomAD Quality Control

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.87

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14631647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3 link	c.12280A>C	p.Lys4094Gln	missense_variant	Exon 66 of 79	ENST00000649046.1	NP_004516.2	P98164Q7Z5C0Q7Z5C1
LRP2	XM_011511183.4 link	c.12151A>C	p.Lys4051Gln	missense_variant	Exon 65 of 78		XP_011509485.1
LRP2	XM_047444340.1 link	c.11356A>C	p.Lys3786Gln	missense_variant	Exon 66 of 79		XP_047300296.1
LRP2	XM_011511184.3 link	c.9991A>C	p.Lys3331Gln	missense_variant	Exon 51 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	ENST00000649046.1 link	c.12280A>C	p.Lys4094Gln	missense_variant	Exon 66 of 79	NM_004525.3	ENSP00000496870.1	P98164
LRP2	ENST00000649153.1 link	n.3178A>C		non_coding_transcript_exon_variant	Exon 18 of 30		ENSP00000497617.1	A0A3B3IT64
LRP2	ENST00000650252.1 link	n.1308A>C		non_coding_transcript_exon_variant	Exon 11 of 24		ENSP00000496887.1	A0A3B3IRR0

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152028

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152028

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74232

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.052

T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.58

.;T

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.15

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

-0.34

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.070

.;N

REVEL

Benign

0.24

Sift

Benign

0.43

.;T

Sift4G

Benign

0.20

.;T

Polyphen

0.0

B;B

Vest4

0.060

MutPred

0.45

Loss of ubiquitination at K4094 (P = 0.0155);Loss of ubiquitination at K4094 (P = 0.0155);

MVP

0.44

MPC

0.72

ClinPred

0.56

GERP RS

5.5

Varity_R

0.11

gMVP

0.65

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over