Genetic Variant LRP2:p.His4385Gln (chr2-169140499-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004525.3(LRP2):c.13155C>A(p.His4385Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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. H4385R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

LRP2
NM_004525.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0810

Publications

2 publications found

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 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

LRP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28959304).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.13155C>A	p.His4385Gln	missense	Exon 72 of 79	NP_004516.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LRP2	ENST00000649046.1	MANE Select	c.13155C>A	p.His4385Gln	missense	Exon 72 of 79	ENSP00000496870.1
LRP2	ENST00000650252.1		n.*829C>A		non_coding_transcript_exon	Exon 17 of 24	ENSP00000496887.1
LRP2	ENST00000650252.1		n.*829C>A		3_prime_UTR	Exon 17 of 24	ENSP00000496887.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251098

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.6

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.15

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.85

M_CAP

Benign

0.012

MetaRNN

Benign

0.29

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

-0.081

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.2

REVEL

Benign

0.075

Sift

Uncertain

0.022

Sift4G

Uncertain

0.021

Polyphen

0.75

Vest4

0.34

MutPred

0.44

Gain of disorder (P = 0.0727)

MVP

0.46

MPC

0.18

ClinPred

0.23

GERP RS

-2.2

Varity_R

0.079

gMVP

0.51

Mutation Taster

=71/29

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over