chr2-169246785-C-T

Variant names:

• chr2-169246785-C-T
• rs147058423
• NM_004525.3:c.3110G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004525.3(LRP2):​c.3110G>A​(p.Arg1037Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,614,196 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.40
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039171368).
• BP6: Variant 2-169246785-C-T is Benign according to our data. Variant chr2-169246785-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211395.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00123 (188/152312) while in subpopulation NFE AF = 0.00219 (149/68032). AF 95% confidence interval is 0.0019. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.3110G>A	p.Arg1037Lys	missense	Exon 21 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.3110G>A	p.Arg1037Lys	missense	Exon 21 of 79	ENSP00000496870.1	P98164
	LRP2	ENST00000443831.1	TSL:2	c.2699G>A	p.Arg900Lys	missense	Exon 19 of 23	ENSP00000409813.1	E9PC35

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00127 AC: 319 AN: 251480 AF XY: 0.00129

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00244

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00196 AC: 2868 AN: 1461884 Hom.: 2 Cov.: 31 AF XY: 0.00196 AC XY: 1423 AN XY: 727242

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00125 AC: 67 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00243 AC: 2703 AN: 1112002

Other (OTH) AF: 0.00136 AC: 82 AN: 60396

GnomAD4 genome AF: 0.00123 AC: 188 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.000967 AC XY: 72 AN XY: 74488

African (AFR) AF: 0.000457 AC: 19 AN: 41576

American (AMR) AF: 0.000719 AC: 11 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00219 AC: 149 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00169 Hom.: 1

Bravo AF: 0.00122

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00151 AC: 183

EpiCase AF: 0.00142

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Donnai-Barrow syndrome (2)
-	-	2	not provided (2)
-	-	1	LRP2-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.039	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.4
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.24
Sift	Benign	0.20	T
Sift4G	Benign	0.31	T
Polyphen		0.0030	B
Vest4		0.061
MVP		0.49
MPC		0.27
ClinPred		0.013	T
GERP RS		2.7
Varity_R		0.10
gMVP		0.60
Mutation Taster		=93/7	polymorphism

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: rs147058423; hg19: chr2-170103295;