rs61995915

Positions:

• chr2-169206467-T-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.7253A>G​(p.Glu2418Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,614,194 control chromosomes in the GnomAD database, including 260 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (23 hom., cov: 32)
  • Exomes 𝑓: 0.016 (237 hom.)
• Consequence: LRP2 NM_004525.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.380

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=0.0028913915).
• BP6: Variant 2-169206467-T-C is Benign according to our data. Variant chr2-169206467-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 259420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169206467-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0124 (1884/152334) while in subpopulation NFE AF= 0.0177 (1203/68034). AF 95% confidence interval is 0.0169. There are 23 homozygotes in gnomad4. There are 977 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.7253A>G	p.Glu2418Gly	missense_variant	39/79	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.7253A>G	p.Glu2418Gly	missense_variant	39/78		XP_011509485.1
LRP2	XM_047444340.1	c.6329A>G	p.Glu2110Gly	missense_variant	39/79		XP_047300296.1
LRP2	XM_011511184.3	c.4964A>G	p.Glu1655Gly	missense_variant	24/64		XP_011509486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.7253A>G	p.Glu2418Gly	missense_variant	39/79		NM_004525.3	ENSP00000496870.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1886 AN: 152216 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.0495

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.0126 AC: 3174 AN: 251320 Hom.: 32 AF XY: 0.0126 AC XY: 1709 AN XY: 135844

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00518

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00601

Gnomad FIN exome AF: 0.0306

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0164 AC: 23948 AN: 1461860 Hom.: 237 Cov.: 33 AF XY: 0.0160 AC XY: 11645 AN XY: 727238

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.00534

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00603

Gnomad4 FIN exome AF: 0.0308

Gnomad4 NFE exome AF: 0.0185

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.0124 AC: 1884 AN: 152334 Hom.: 23 Cov.: 32 AF XY: 0.0131 AC XY: 977 AN XY: 74498

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0332

Gnomad4 NFE AF: 0.0177

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.0150 Hom.: 33

Bravo AF: 0.0103

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0167 AC: 144

ExAC AF: 0.0129 AC: 1561

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0171

EpiControl AF: 0.0149

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Donnai-Barrow syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 27, 2021	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.35
DANN	Benign	0.37
DEOGEN2	Benign	0.094	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.30	.;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.38	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.96	.;N
REVEL	Benign	0.16
Sift	Benign	0.47	.;T
Sift4G	Benign	0.62	.;T
Polyphen		0.0010	B;B
Vest4		0.032
MPC		0.28
ClinPred		0.00073	T
GERP RS		0.59
Varity_R		0.027
gMVP		0.39

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: rs61995915; hg19: chr2-170062977; COSMIC: COSV104378670;