rs853988

Variant names:

• chr2-169303851-C-A
• rs853988
• NM_004525.3:c.427+3430G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-169303851-C-A
• chr2-169303851-C-G
• chr2-169303851-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004525.3(LRP2):​c.427+3430G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 151,894 control chromosomes in the GnomAD database, including 26,093 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.57 (26093 hom., cov: 31)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.884
• Publications: 8 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Stickler syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2	NM_004525.3	c.427+3430G>T		intron_variant	Intron 4 of 78	ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.427+3430G>T		intron_variant	Intron 4 of 77		XP_011509485.1
LRP2	XM_047444340.1	c.-498+3430G>T		intron_variant	Intron 4 of 78		XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.427+3430G>T		intron_variant	Intron 4 of 78		NM_004525.3	ENSP00000496870.1
LRP2	ENST00000443831.1	c.427+3430G>T		intron_variant	Intron 4 of 22	2		ENSP00000409813.1

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86449 AN: 151776 Hom.: 26047 Cov.: 31

Gnomad AFR AF: 0.768

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.559

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.573

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.570 AC: 86554 AN: 151894 Hom.: 26093 Cov.: 31 AF XY: 0.571 AC XY: 42382 AN XY: 74216

African (AFR) AF: 0.768 AC: 31826 AN: 41442

American (AMR) AF: 0.651 AC: 9944 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1694 AN: 3468

East Asian (EAS) AF: 0.558 AC: 2879 AN: 5158

South Asian (SAS) AF: 0.455 AC: 2186 AN: 4800

European-Finnish (FIN) AF: 0.483 AC: 5090 AN: 10538

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.460 AC: 31263 AN: 67920

Other (OTH) AF: 0.569 AC: 1197 AN: 2102

Alfa AF: 0.485 Hom.: 28243

Bravo AF: 0.594

Asia WGS AF: 0.520 AC: 1806 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.6
DANN	Benign	0.61
PhyloP100		-0.88
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: rs853988; hg19: chr2-170160361;