rs114460450

Positions:

• chr2-169320815-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004525.3(LRP2):​c.149C>G​(p.Thr50Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00315 in 1,614,036 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (30 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 5.38

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP2. . Trascript score misZ 4.5094 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, Stickler syndrome, Donnai-Barrow syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0073717237).
• BP6: Variant 2-169320815-G-C is Benign according to our data. Variant chr2-169320815-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 332208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169320815-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00324 (493/152206) while in subpopulation NFE AF= 0.00309 (210/68026). AF 95% confidence interval is 0.00274. There are 5 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.149C>G	p.Thr50Ser	missense_variant	2/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.149C>G	p.Thr50Ser	missense_variant	2/78		XP_011509485.1
LRP2	XM_047444340.1	c.-776C>G		5_prime_UTR_variant	2/79		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.149C>G	p.Thr50Ser	missense_variant	2/79		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.149C>G	p.Thr50Ser	missense_variant	2/23	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.00324 AC: 493 AN: 152088 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00377 AC: 947 AN: 251470 Hom.: 11 AF XY: 0.00369 AC XY: 501 AN XY: 135914

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0241

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00314 AC: 4594 AN: 1461830 Hom.: 30 Cov.: 31 AF XY: 0.00305 AC XY: 2217 AN XY: 727226

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0218

Gnomad4 NFE exome AF: 0.00288

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.00324 AC: 493 AN: 152206 Hom.: 5 Cov.: 33 AF XY: 0.00403 AC XY: 300 AN XY: 74416

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0226

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00227 Hom.: 0

Bravo AF: 0.00168

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00342 AC: 415

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	LRP2: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Donnai-Barrow syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Hearing loss and Retinal dystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

research

National Institute on Deafness and Communication Disorders, National Institutes of Health

Feb 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	.;D;D
MetaRNN	Benign	0.0074	T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.69	N;N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.99	.;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.21	.;T;T
Sift4G	Uncertain	0.015	.;D;T
Polyphen		0.83	P;P;P
Vest4		0.30, 0.41
MutPred		0.45		Gain of disorder (P = 0.034);Gain of disorder (P = 0.034);Gain of disorder (P = 0.034);
MVP		0.57
MPC		0.59
ClinPred		0.051	T
GERP RS		2.0
Varity_R		0.052
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: rs114460450; hg19: chr2-170177325; COSMIC: COSV104378838;