chr2-169154475-T-G

Variant names:

• chr2-169154475-T-G
• NM_004525.3:c.12280A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.87

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]

ACMG classification

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	c.12280A>C	p.Lys4094Gln	missense_variant	Exon 66 of 79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.12151A>C	p.Lys4051Gln	missense_variant	Exon 65 of 78		XP_011509485.1
LRP2	XM_047444340.1	c.11356A>C	p.Lys3786Gln	missense_variant	Exon 66 of 79		XP_047300296.1
LRP2	XM_011511184.3	c.9991A>C	p.Lys3331Gln	missense_variant	Exon 51 of 64		XP_011509486.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152028 Hom.: 0 Cov.: 31 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.: 39

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152028 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Benign	0.052	T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.58	.;T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	-0.34	N;N
PrimateAI	Benign	0.33	T
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	D
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.

Other links and lift over

hg19: chr2-170010985;