2-169204093-T-C

Variant names:

• chr2-169204093-T-C
• rs17848169
• NM_004525.3:c.7894A>G

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.7894A>G​(p.Asn2632Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 1,614,116 control chromosomes in the GnomAD database, including 1,143 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. N2632H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.026 (66 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1077 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.33
• Publications: 26 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=0.0028695464).
• BP6: Variant 2-169204093-T-C is Benign according to our data. Variant chr2-169204093-T-C is described in ClinVar as Benign. ClinVar VariationId is 129540.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 = 0.0262 (3984/152252) while in subpopulation NFE AF = 0.0378 (2573/68002). AF 95% confidence interval is 0.0366. There are 66 homozygotes in GnomAd4. There are 1970 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 66 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.7894A>G	p.Asn2632Asp	missense	Exon 42 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.7894A>G	p.Asn2632Asp	missense	Exon 42 of 79	ENSP00000496870.1	P98164

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3986 AN: 152134 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.00666

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.0280

Gnomad FIN AF: 0.0452

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0379

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0292 AC: 7349 AN: 251404 AF XY: 0.0306

Gnomad AFR exome AF: 0.00603

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.0227

Gnomad EAS exome AF: 0.0140

Gnomad FIN exome AF: 0.0434

Gnomad NFE exome AF: 0.0369

Gnomad OTH exome AF: 0.0318

GnomAD4 exome AF: 0.0365 AC: 53385 AN: 1461864 Hom.: 1077 Cov.: 33 AF XY: 0.0366 AC XY: 26582 AN XY: 727240

African (AFR) AF: 0.00517 AC: 173 AN: 33480

American (AMR) AF: 0.0133 AC: 594 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0197 AC: 514 AN: 26136

East Asian (EAS) AF: 0.0142 AC: 564 AN: 39700

South Asian (SAS) AF: 0.0336 AC: 2901 AN: 86258

European-Finnish (FIN) AF: 0.0414 AC: 2211 AN: 53420

Middle Eastern (MID) AF: 0.0192 AC: 111 AN: 5768

European-Non Finnish (NFE) AF: 0.0399 AC: 44383 AN: 1111984

Other (OTH) AF: 0.0320 AC: 1934 AN: 60394

GnomAD4 genome AF: 0.0262 AC: 3984 AN: 152252 Hom.: 66 Cov.: 32 AF XY: 0.0265 AC XY: 1970 AN XY: 74448

African (AFR) AF: 0.00664 AC: 276 AN: 41548

American (AMR) AF: 0.0165 AC: 253 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3470

East Asian (EAS) AF: 0.0158 AC: 82 AN: 5184

South Asian (SAS) AF: 0.0280 AC: 135 AN: 4824

European-Finnish (FIN) AF: 0.0452 AC: 480 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0378 AC: 2573 AN: 68002

Other (OTH) AF: 0.0161 AC: 34 AN: 2110

Alfa AF: 0.0327 Hom.: 297

Bravo AF: 0.0233

TwinsUK AF: 0.0461 AC: 171

ALSPAC AF: 0.0400 AC: 154

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0374 AC: 322

ExAC AF: 0.0295 AC: 3582

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0374

EpiControl AF: 0.0358

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	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.7
DANN	Benign	0.45
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.98	L
PhyloP100		2.3
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.27
Sift	Benign	0.73	T
Sift4G	Benign	0.56	T
Polyphen		0.51	P
Vest4		0.043
MPC		0.27
ClinPred		0.0096	T
GERP RS		3.1
Varity_R		0.078
gMVP		0.41
Mutation Taster		=93/7	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: rs17848169; hg19: chr2-170060603; COSMIC: COSV55555945;