NM_004525.3:c.775G>C

Variant names:

• chr2-169290992-C-G
• rs34693334
• NM_004525.3:c.775G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004525.3(LRP2):​c.775G>C​(p.Gly259Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0651 in 1,613,654 control chromosomes in the GnomAD database, including 4,153 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G259S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.056 (353 hom., cov: 31)
  • Exomes 𝑓: 0.066 (3800 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.687
• Publications: 19 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Stickler syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• congenital heart disease

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017864704).
• BP6: Variant 2-169290992-C-G is Benign according to our data. Variant chr2-169290992-C-G is described in ClinVar as Benign. ClinVar VariationId is 129539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0708 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.775G>C	p.Gly259Arg	missense	Exon 8 of 79	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.775G>C	p.Gly259Arg	missense	Exon 8 of 79	ENSP00000496870.1	P98164
	LRP2	ENST00000443831.1	TSL:2	c.775G>C	p.Gly259Arg	missense	Exon 8 of 23	ENSP00000409813.1	E9PC35

Frequencies

GnomAD3 genomes AF: 0.0557 AC: 8475 AN: 152048 Hom.: 354 Cov.: 31

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0772

Gnomad FIN AF: 0.0874

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.0697

Gnomad OTH AF: 0.0621

GnomAD2 exomes AF: 0.0637 AC: 15985 AN: 250840 AF XY: 0.0665

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.0345

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.000979

Gnomad FIN exome AF: 0.0832

Gnomad NFE exome AF: 0.0691

Gnomad OTH exome AF: 0.0827

GnomAD4 exome AF: 0.0661 AC: 96590 AN: 1461488 Hom.: 3800 Cov.: 32 AF XY: 0.0677 AC XY: 49187 AN XY: 727040

African (AFR) AF: 0.0202 AC: 675 AN: 33468

American (AMR) AF: 0.0367 AC: 1641 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4715 AN: 26130

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39696

South Asian (SAS) AF: 0.0854 AC: 7365 AN: 86218

European-Finnish (FIN) AF: 0.0837 AC: 4469 AN: 53412

Middle Eastern (MID) AF: 0.123 AC: 711 AN: 5764

European-Non Finnish (NFE) AF: 0.0654 AC: 72724 AN: 1111704

Other (OTH) AF: 0.0707 AC: 4270 AN: 60382

GnomAD4 genome AF: 0.0557 AC: 8475 AN: 152166 Hom.: 353 Cov.: 31 AF XY: 0.0567 AC XY: 4214 AN XY: 74384

African (AFR) AF: 0.0203 AC: 843 AN: 41536

American (AMR) AF: 0.0492 AC: 752 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 629 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5180

South Asian (SAS) AF: 0.0773 AC: 371 AN: 4802

European-Finnish (FIN) AF: 0.0874 AC: 924 AN: 10570

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.0697 AC: 4739 AN: 68000

Other (OTH) AF: 0.0610 AC: 129 AN: 2114

Alfa AF: 0.0698 Hom.: 388

Bravo AF: 0.0510

TwinsUK AF: 0.0677 AC: 251

ALSPAC AF: 0.0636 AC: 245

ESP6500AA AF: 0.0254 AC: 112

ESP6500EA AF: 0.0707 AC: 608

ExAC AF: 0.0630 AC: 7655

Asia WGS AF: 0.0340 AC: 119 AN: 3478

EpiCase AF: 0.0728

EpiControl AF: 0.0741

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Donnai-Barrow syndrome (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.4
DANN	Benign	0.44
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.69
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.077
Sift	Benign	0.54	T
Sift4G	Uncertain	0.060	T
Polyphen		0.013	B
Vest4		0.080
MPC		0.28
ClinPred		0.0018	T
GERP RS		2.7
Varity_R		0.030
gMVP		0.47
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs34693334; hg19: chr2-170147502; COSMIC: COSV55539090;