2-169242936-T-G

Variant names:

• chr2-169242936-T-G
• rs831041
• NM_004525.3:c.3667+20A>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.3667+20A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,543,352 control chromosomes in the GnomAD database, including 186,756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23267 hom., cov: 32)
  • Exomes 𝑓: 0.48 (163489 hom.)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.00
• Publications: 13 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=-0.85).
• BP6: Variant 2-169242936-T-G is Benign according to our data. Variant chr2-169242936-T-G is described in ClinVar as Benign. ClinVar VariationId is 259416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.727 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.3667+20A>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.3667+20A>C		intron	N/A	ENSP00000496870.1	P98164
	LRP2	ENST00000443831.1	TSL:2	c.3256+20A>C		intron	N/A	ENSP00000409813.1	E9PC35

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82321 AN: 151898 Hom.: 23232 Cov.: 32

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.540

GnomAD2 exomes AF: 0.538 AC: 135183 AN: 251394 AF XY: 0.540

Gnomad AFR exome AF: 0.698

Gnomad AMR exome AF: 0.673

Gnomad ASJ exome AF: 0.542

Gnomad EAS exome AF: 0.475

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.458

Gnomad OTH exome AF: 0.497

GnomAD4 exome AF: 0.475 AC: 661245 AN: 1391336 Hom.: 163489 Cov.: 23 AF XY: 0.484 AC XY: 336971 AN XY: 696652

African (AFR) AF: 0.690 AC: 21948 AN: 31786

American (AMR) AF: 0.663 AC: 29583 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 13398 AN: 25668

East Asian (EAS) AF: 0.455 AC: 17894 AN: 39308

South Asian (SAS) AF: 0.739 AC: 62400 AN: 84420

European-Finnish (FIN) AF: 0.387 AC: 20651 AN: 53364

Middle Eastern (MID) AF: 0.539 AC: 3042 AN: 5640

European-Non Finnish (NFE) AF: 0.442 AC: 463581 AN: 1048534

Other (OTH) AF: 0.496 AC: 28748 AN: 57988

GnomAD4 genome AF: 0.542 AC: 82412 AN: 152016 Hom.: 23267 Cov.: 32 AF XY: 0.544 AC XY: 40381 AN XY: 74292

African (AFR) AF: 0.691 AC: 28639 AN: 41458

American (AMR) AF: 0.597 AC: 9114 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1769 AN: 3466

East Asian (EAS) AF: 0.476 AC: 2447 AN: 5146

South Asian (SAS) AF: 0.747 AC: 3602 AN: 4822

European-Finnish (FIN) AF: 0.383 AC: 4049 AN: 10578

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.457 AC: 31070 AN: 67968

Other (OTH) AF: 0.544 AC: 1151 AN: 2114

Alfa AF: 0.481 Hom.: 22656

Bravo AF: 0.560

Asia WGS AF: 0.649 AC: 2256 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.030
DANN	Benign	0.27
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs831041; hg19: chr2-170099446;