NM_004525.3:c.2006G>A

Variant names:

• chr2-169273037-C-T
• rs34291900
• NM_004525.3:c.2006G>A
• LRP2 p.Gly669Asp

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004525.3(LRP2):​c.2006G>A​(p.Gly669Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0334 in 1,613,540 control chromosomes in the GnomAD database, including 1,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G669G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.025 (62 hom., cov: 34)
  • Exomes 𝑓: 0.034 (978 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 7.79
• Publications: 20 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 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=0.012386203).
• BP6: Variant 2-169273037-C-T is Benign according to our data. Variant chr2-169273037-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0249 (3787/152260) while in subpopulation NFE AF = 0.0362 (2460/68026). AF 95% confidence interval is 0.035. There are 62 homozygotes in GnomAd4. There are 1895 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 62 AD,AR gene

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.2006G>A	p.Gly669Asp	missense	Exon 15 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.2006G>A	p.Gly669Asp	missense	Exon 15 of 79	ENSP00000496870.1	P98164
	LRP2	ENST00000443831.1	TSL:2	c.1799G>A	p.Gly600Asp	missense	Exon 14 of 23	ENSP00000409813.1	E9PC35
	LRP2	ENST00000493501.1	TSL:4	n.349G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3790 AN: 152142 Hom.: 62 Cov.: 34

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.0202

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0274

Gnomad FIN AF: 0.0455

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0362

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0280 AC: 7012 AN: 250820 AF XY: 0.0294

Gnomad AFR exome AF: 0.00566

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0447

Gnomad NFE exome AF: 0.0352

Gnomad OTH exome AF: 0.0317

GnomAD4 exome AF: 0.0343 AC: 50082 AN: 1461280 Hom.: 978 Cov.: 37 AF XY: 0.0345 AC XY: 25046 AN XY: 726948

African (AFR) AF: 0.00484 AC: 162 AN: 33440

American (AMR) AF: 0.0143 AC: 637 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.0232 AC: 606 AN: 26108

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0340 AC: 2929 AN: 86252

European-Finnish (FIN) AF: 0.0431 AC: 2299 AN: 53400

Middle Eastern (MID) AF: 0.0182 AC: 105 AN: 5758

European-Non Finnish (NFE) AF: 0.0373 AC: 41510 AN: 1111624

Other (OTH) AF: 0.0304 AC: 1832 AN: 60360

GnomAD4 genome AF: 0.0249 AC: 3787 AN: 152260 Hom.: 62 Cov.: 34 AF XY: 0.0255 AC XY: 1895 AN XY: 74422

African (AFR) AF: 0.00570 AC: 237 AN: 41556

American (AMR) AF: 0.0202 AC: 309 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0274 AC: 132 AN: 4822

European-Finnish (FIN) AF: 0.0455 AC: 482 AN: 10602

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0362 AC: 2460 AN: 68026

Other (OTH) AF: 0.0175 AC: 37 AN: 2116

Alfa AF: 0.0318 Hom.: 243

Bravo AF: 0.0217

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0354

EpiControl AF: 0.0336

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Donnai-Barrow syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.91
gMVP		0.76
Mutation Taster		=55/45	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34291900;

hg19: chr2-170129547;