2-169196995-C-T

Variant names:

• chr2-169196995-C-T
• rs2228171
• NM_004525.3:c.8614G>A

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.8614G>A​(p.Ala2872Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,604 control chromosomes in the GnomAD database, including 61,712 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (5331 hom., cov: 33)
  • Exomes 𝑓: 0.27 (56381 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.28
• Publications: 54 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2853743E-5).
• BP6: Variant 2-169196995-C-T is Benign according to our data. Variant chr2-169196995-C-T is described in ClinVar as Benign. ClinVar VariationId is 129542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.526 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.8614G>A	p.Ala2872Thr	missense	Exon 46 of 79	NP_004516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.8614G>A	p.Ala2872Thr	missense	Exon 46 of 79	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38454 AN: 152042 Hom.: 5331 Cov.: 33

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.544

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.267 AC: 67115 AN: 251132 AF XY: 0.263

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.560

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.270 AC: 394385 AN: 1461444 Hom.: 56381 Cov.: 35 AF XY: 0.267 AC XY: 194018 AN XY: 727046

African (AFR) AF: 0.199 AC: 6661 AN: 33474

American (AMR) AF: 0.175 AC: 7831 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7326 AN: 26136

East Asian (EAS) AF: 0.560 AC: 22237 AN: 39696

South Asian (SAS) AF: 0.165 AC: 14274 AN: 86250

European-Finnish (FIN) AF: 0.356 AC: 18939 AN: 53260

Middle Eastern (MID) AF: 0.206 AC: 1184 AN: 5760

European-Non Finnish (NFE) AF: 0.269 AC: 299545 AN: 1111766

Other (OTH) AF: 0.271 AC: 16388 AN: 60378

GnomAD4 genome AF: 0.253 AC: 38461 AN: 152160 Hom.: 5331 Cov.: 33 AF XY: 0.254 AC XY: 18916 AN XY: 74374

African (AFR) AF: 0.196 AC: 8132 AN: 41512

American (AMR) AF: 0.185 AC: 2837 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1027 AN: 3468

East Asian (EAS) AF: 0.543 AC: 2807 AN: 5172

South Asian (SAS) AF: 0.172 AC: 828 AN: 4828

European-Finnish (FIN) AF: 0.359 AC: 3792 AN: 10568

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18147 AN: 67994

Other (OTH) AF: 0.231 AC: 488 AN: 2112

Alfa AF: 0.264 Hom.: 15428

Bravo AF: 0.241

TwinsUK AF: 0.268 AC: 993

ALSPAC AF: 0.287 AC: 1105

ESP6500AA AF: 0.194 AC: 855

ESP6500EA AF: 0.263 AC: 2261

ExAC AF: 0.267 AC: 32470

Asia WGS AF: 0.312 AC: 1086 AN: 3478

EpiCase AF: 0.256

EpiControl AF: 0.247

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Donnai-Barrow syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.77
DANN	Benign	0.60
DEOGEN2	Benign	0.16	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.000023	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.17	N
PhyloP100		-1.3
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.92	N
REVEL	Benign	0.23
Sift	Benign	0.96	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.23
ClinPred		0.0087	T
GERP RS		-11
Varity_R		0.024
gMVP		0.29
Mutation Taster		=95/5	polymorphism (auto)

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: rs2228171; hg19: chr2-170053505; COSMIC: COSV55542084;