rs80338746

Variant names:

• chr2-169247447-T-C
• rs80338746
• NM_004525.3:c.2839A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004525.3(LRP2):​c.2839A>G​(p.Met947Val) 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.984
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053349853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.2839A>G	p.Met947Val	missense_variant	Exon 20 of 79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.2839A>G	p.Met947Val	missense_variant	Exon 20 of 78		XP_011509485.1
LRP2	XM_047444340.1	c.1915A>G	p.Met639Val	missense_variant	Exon 20 of 79		XP_047300296.1
LRP2	XM_011511184.3	c.550A>G	p.Met184Val	missense_variant	Exon 5 of 64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.2839A>G	p.Met947Val	missense_variant	Exon 20 of 79		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.2428A>G	p.Met810Val	missense_variant	Exon 18 of 23	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000431 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.40
DANN	Benign	0.31
DEOGEN2	Benign	0.058	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.74	.;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.41	N;N;.
PhyloP100		0.98
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.83	.;N;N
REVEL	Benign	0.10
Sift	Benign	0.29	.;T;T
Sift4G	Benign	0.20	.;T;T
Polyphen		0.0010	B;B;B
Vest4		0.17, 0.21
MutPred		0.33		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;
MVP		0.38
MPC		0.24
ClinPred		0.21	T
GERP RS		-2.7
Varity_R		0.043
gMVP		0.38
Mutation Taster		=87/13	polymorphism

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: rs80338746; hg19: chr2-170103957;