2-169156300-C-T

Position:

• chr2-169156300-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_004525.3(LRP2):​c.12125G>A​(p.Arg4042His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00051 in 1,613,718 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4042C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (10 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.712

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRP2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0037784576).
• BP6: Variant 2-169156300-C-T is Benign according to our data. Variant chr2-169156300-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129498.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=1}. Variant chr2-169156300-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000361 (55/152254) while in subpopulation SAS AF= 0.0058 (28/4826). AF 95% confidence interval is 0.00412. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP2	NM_004525.3	c.12125G>A	p.Arg4042His	missense_variant	65/79	ENST00000649046.1
LRP2	XM_011511183.4	c.11996G>A	p.Arg3999His	missense_variant	64/78
LRP2	XM_047444340.1	c.11201G>A	p.Arg3734His	missense_variant	65/79
LRP2	XM_011511184.3	c.9836G>A	p.Arg3279His	missense_variant	50/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP2	ENST00000649046.1	c.12125G>A	p.Arg4042His	missense_variant	65/79		NM_004525.3	P1
LRP2	ENST00000649153.1	c.3026G>A	p.Arg1009His	missense_variant, NMD_transcript_variant	17/30
LRP2	ENST00000650252.1	c.1157G>A	p.Arg386His	missense_variant, NMD_transcript_variant	10/24

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00110 AC: 277 AN: 251398 Hom.: 6 AF XY: 0.00139 AC XY: 189 AN XY: 135872

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00777

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000526 AC: 768 AN: 1461464 Hom.: 10 Cov.: 31 AF XY: 0.000723 AC XY: 526 AN XY: 727050

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00686

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000837

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74448

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000195 Hom.: 0

Bravo AF: 0.000185

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00120 AC: 146

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 25, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	LRP2: BP4, BS2 -

Donnai-Barrow syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.011
DANN	Benign	0.57
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.019	N
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.84	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
Polyphen		0.010	B;B
Vest4		0.060
MVP		0.42
MPC		0.84
ClinPred		0.020	T
GERP RS		-12
Varity_R		0.019
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs199874294; hg19: chr2-170012810; COSMIC: COSV55545355;