chr2-169147128-G-A

Position:

• chr2-169147128-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004525.3(LRP2):​c.12591-169C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 151,974 control chromosomes in the GnomAD database, including 19,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.50 (19791 hom., cov: 32)
• Consequence: LRP2 NM_004525.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.156

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-169147128-G-A is Benign according to our data. Variant chr2-169147128-G-A is described in ClinVar as [Benign]. Clinvar id is 1231582.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP2	NM_004525.3	c.12591-169C>T		intron_variant		ENST00000649046.1	NP_004516.2
LRP2	XM_011511183.4	c.12462-169C>T		intron_variant			XP_011509485.1
LRP2	XM_011511184.3	c.10302-169C>T		intron_variant			XP_011509486.1
LRP2	XM_047444340.1	c.11667-169C>T		intron_variant			XP_047300296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP2	ENST00000649046.1	c.12591-169C>T		intron_variant			NM_004525.3	ENSP00000496870	P1
LRP2	ENST00000649153.1	c.3491-169C>T		intron_variant, NMD_transcript_variant				ENSP00000497617
LRP2	ENST00000650252.1	c.*302-169C>T		intron_variant, NMD_transcript_variant				ENSP00000496887

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76436 AN: 151856 Hom.: 19776 Cov.: 32

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.494

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

GnomAD4 genome AF: 0.503 AC: 76498 AN: 151974 Hom.: 19791 Cov.: 32 AF XY: 0.501 AC XY: 37209 AN XY: 74256

Gnomad4 AFR AF: 0.540

Gnomad4 AMR AF: 0.614

Gnomad4 ASJ AF: 0.463

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.461

Gnomad4 FIN AF: 0.446

Gnomad4 NFE AF: 0.501

Gnomad4 OTH AF: 0.493

Alfa AF: 0.450 Hom.: 2613

Bravo AF: 0.517

Asia WGS AF: 0.359 AC: 1252 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.49

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: rs4667592; hg19: chr2-170003638; COSMIC: COSV104378330;