rs61995915

Variant names:

• chr2-169206467-T-C
• rs61995915
• NM_004525.3:c.7253A>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.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. 16/21 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
• Publications: 11 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=0.0028913915).
• BP6: Variant 2-169206467-T-C is Benign according to our data. Variant chr2-169206467-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259420.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 = 0.0124 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR,AD 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.7253A>G	p.Glu2418Gly	missense	Exon 39 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.7253A>G	p.Glu2418Gly	missense	Exon 39 of 79	ENSP00000496870.1	P98164

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

GnomAD2 exomes AF: 0.0126 AC: 3174 AN: 251320 AF XY: 0.0126

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 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

African (AFR) AF: 0.00221 AC: 74 AN: 33480

American (AMR) AF: 0.00534 AC: 239 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 63 AN: 26136

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

South Asian (SAS) AF: 0.00603 AC: 520 AN: 86258

European-Finnish (FIN) AF: 0.0308 AC: 1646 AN: 53416

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0185 AC: 20573 AN: 1111986

Other (OTH) AF: 0.0135 AC: 817 AN: 60396

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

African (AFR) AF: 0.00279 AC: 116 AN: 41570

American (AMR) AF: 0.00856 AC: 131 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4828

European-Finnish (FIN) AF: 0.0332 AC: 353 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0177 AC: 1203 AN: 68034

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.0152 Hom.: 59

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Donnai-Barrow syndrome (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.38	N
PhyloP100		0.38
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
Vest4		0.032
MPC		0.28
ClinPred		0.00073	T
GERP RS		0.59
Varity_R		0.027
gMVP		0.39
Mutation Taster		=99/1	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: rs61995915; hg19: chr2-170062977;