NM_004525.3:c.12628A>C

Variant names:

• chr2-169146922-T-G
• rs4667591
• NM_004525.3:c.12628A>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.12628A>C​(p.Ile4210Leu) variant causes a missense change. The variant allele was found at a frequency of 0.751 in 1,613,220 control chromosomes in the GnomAD database, including 468,969 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I4210I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.62 (33571 hom., cov: 31)
  • Exomes 𝑓: 0.76 (435398 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 6.26
• Publications: 64 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=3.6997403E-6).
• BP6: Variant 2-169146922-T-G is Benign according to our data. Variant chr2-169146922-T-G is described in ClinVar as Benign. ClinVar VariationId is 129501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.785 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.12628A>C	p.Ile4210Leu	missense	Exon 69 of 79	NP_004516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.12628A>C	p.Ile4210Leu	missense	Exon 69 of 79	ENSP00000496870.1
	LRP2	ENST00000649153.1		n.3526A>C		non_coding_transcript_exon	Exon 21 of 30	ENSP00000497617.1
	LRP2	ENST00000650252.1		n.*339A>C		non_coding_transcript_exon	Exon 14 of 24	ENSP00000496887.1

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93883 AN: 151832 Hom.: 33565 Cov.: 31

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.737

Gnomad ASJ AF: 0.843

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.727

Gnomad MID AF: 0.780

Gnomad NFE AF: 0.790

Gnomad OTH AF: 0.684

GnomAD2 exomes AF: 0.724 AC: 181286 AN: 250362 AF XY: 0.740

Gnomad AFR exome AF: 0.223

Gnomad AMR exome AF: 0.781

Gnomad ASJ exome AF: 0.843

Gnomad EAS exome AF: 0.461

Gnomad FIN exome AF: 0.733

Gnomad NFE exome AF: 0.785

Gnomad OTH exome AF: 0.758

GnomAD4 exome AF: 0.765 AC: 1117297 AN: 1461270 Hom.: 435398 Cov.: 53 AF XY: 0.768 AC XY: 558561 AN XY: 726924

African (AFR) AF: 0.211 AC: 7063 AN: 33474

American (AMR) AF: 0.776 AC: 34667 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.845 AC: 22076 AN: 26136

East Asian (EAS) AF: 0.470 AC: 18613 AN: 39634

South Asian (SAS) AF: 0.804 AC: 69319 AN: 86240

European-Finnish (FIN) AF: 0.729 AC: 38896 AN: 53362

Middle Eastern (MID) AF: 0.789 AC: 4547 AN: 5766

European-Non Finnish (NFE) AF: 0.790 AC: 877781 AN: 1111626

Other (OTH) AF: 0.734 AC: 44335 AN: 60366

GnomAD4 genome AF: 0.618 AC: 93903 AN: 151950 Hom.: 33571 Cov.: 31 AF XY: 0.620 AC XY: 46053 AN XY: 74274

African (AFR) AF: 0.233 AC: 9635 AN: 41378

American (AMR) AF: 0.737 AC: 11262 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.843 AC: 2925 AN: 3470

East Asian (EAS) AF: 0.477 AC: 2458 AN: 5158

South Asian (SAS) AF: 0.795 AC: 3831 AN: 4820

European-Finnish (FIN) AF: 0.727 AC: 7693 AN: 10582

Middle Eastern (MID) AF: 0.788 AC: 230 AN: 292

European-Non Finnish (NFE) AF: 0.790 AC: 53722 AN: 67960

Other (OTH) AF: 0.684 AC: 1440 AN: 2106

Alfa AF: 0.735 Hom.: 158444

Bravo AF: 0.596

TwinsUK AF: 0.788 AC: 2922

ALSPAC AF: 0.782 AC: 3012

ESP6500AA AF: 0.242 AC: 1067

ESP6500EA AF: 0.790 AC: 6795

ExAC AF: 0.711 AC: 86367

Asia WGS AF: 0.644 AC: 2239 AN: 3478

EpiCase AF: 0.803

EpiControl AF: 0.806

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0000037	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.16
MPC		1.7
ClinPred		0.055	T
GERP RS		4.5
Varity_R		0.73
gMVP		0.96
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4667591; hg19: chr2-170003432; COSMIC: COSV55550820;