2-169292235-A-G

Variant names:

• chr2-169292235-A-G
• rs62171262
• NM_004525.3:c.769+18T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004525.3(LRP2):​c.769+18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0639 in 1,520,040 control chromosomes in the GnomAD database, including 3,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (335 hom., cov: 31)
  • Exomes 𝑓: 0.065 (3480 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.27
• Publications: 5 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 (BayesDel_noAF=-0.84).
• BP6: Variant 2-169292235-A-G is Benign according to our data. Variant chr2-169292235-A-G is described in ClinVar as Benign. ClinVar VariationId is 259421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0705 is higher than 0.05.

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.769+18T>C		intron	N/A	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.769+18T>C		intron	N/A	ENSP00000496870.1	P98164
	LRP2	ENST00000443831.1	TSL:2	c.769+18T>C		intron	N/A	ENSP00000409813.1	E9PC35

Frequencies

GnomAD3 genomes AF: 0.0543 AC: 8259 AN: 152092 Hom.: 336 Cov.: 31

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0480

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0768

Gnomad FIN AF: 0.0825

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.0681

Gnomad OTH AF: 0.0619

GnomAD2 exomes AF: 0.0625 AC: 15690 AN: 251058 AF XY: 0.0654

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.000979

Gnomad FIN exome AF: 0.0796

Gnomad NFE exome AF: 0.0672

Gnomad OTH exome AF: 0.0815

GnomAD4 exome AF: 0.0650 AC: 88929 AN: 1367828 Hom.: 3480 Cov.: 21 AF XY: 0.0667 AC XY: 45757 AN XY: 686116

African (AFR) AF: 0.0199 AC: 629 AN: 31596

American (AMR) AF: 0.0365 AC: 1626 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 4642 AN: 25548

East Asian (EAS) AF: 0.000484 AC: 19 AN: 39264

South Asian (SAS) AF: 0.0856 AC: 7226 AN: 84372

European-Finnish (FIN) AF: 0.0799 AC: 4261 AN: 53354

Middle Eastern (MID) AF: 0.124 AC: 690 AN: 5586

European-Non Finnish (NFE) AF: 0.0642 AC: 65847 AN: 1026268

Other (OTH) AF: 0.0697 AC: 3989 AN: 57244

GnomAD4 genome AF: 0.0543 AC: 8259 AN: 152212 Hom.: 335 Cov.: 31 AF XY: 0.0550 AC XY: 4092 AN XY: 74416

African (AFR) AF: 0.0194 AC: 805 AN: 41528

American (AMR) AF: 0.0479 AC: 733 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 628 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5176

South Asian (SAS) AF: 0.0770 AC: 371 AN: 4818

European-Finnish (FIN) AF: 0.0825 AC: 875 AN: 10600

Middle Eastern (MID) AF: 0.140 AC: 41 AN: 292

European-Non Finnish (NFE) AF: 0.0681 AC: 4633 AN: 68016

Other (OTH) AF: 0.0608 AC: 128 AN: 2106

Alfa AF: 0.0717 Hom.: 178

Bravo AF: 0.0498

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.2
DANN	Benign	0.64
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs62171262; hg19: chr2-170148745;