12-12124372-C-CA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002336.3(LRP6):c.4547+192_4547+193insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0752 in 151,708 control chromosomes in the GnomAD database, including 509 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.075 (509 hom., cov: 31)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.620

Genes affected

LRP6 (HGNC:6698): (LDL receptor related protein 6) This gene encodes a member of the low density lipoprotein (LDL) receptor gene family. LDL receptors are transmembrane cell surface proteins involved in receptor-mediated endocytosis of lipoprotein and protein ligands. The protein encoded by this gene functions as a receptor or, with Frizzled, a co-receptor for Wnt and thereby transmits the canonical Wnt/beta-catenin signaling cascade. Through its interaction with the Wnt/beta-catenin signaling cascade this gene plays a role in the regulation of cell differentiation, proliferation, and migration and the development of many cancer types. This protein undergoes gamma-secretase dependent RIP- (regulated intramembrane proteolysis) processing but the precise locations of the cleavage sites have not been determined.[provided by RefSeq, Dec 2009]

BCL2L14 (HGNC:16657): (BCL2 like 14) The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. Overexpression of this gene has been shown to induce apoptosis in cells. Three alternatively spliced transcript variants encoding two distinct isoforms have been reported for this gene. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 12-12124372-C-CA is Benign according to our data. Variant chr12-12124372-C-CA is described in ClinVar as [Benign]. Clinvar id is 1289846.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP6	NM_002336.3	c.4547+192_4547+193insT		intron_variant		ENST00000261349.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP6	ENST00000261349.9	c.4547+192_4547+193insT		intron_variant		1	NM_002336.3	P1

Frequencies

GnomAD3 genomes AF: 0.0752 AC: 11405 AN: 151588 Hom.: 509 Cov.: 31

Gnomad AFR AF: 0.0457

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0890

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0393

Gnomad FIN AF: 0.0737

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0924

Gnomad OTH AF: 0.0870

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

GnomAD4 genome AF: 0.0752 AC: 11406 AN: 151708 Hom.: 509 Cov.: 31 AF XY: 0.0742 AC XY: 5497 AN XY: 74092

Gnomad4 AFR AF: 0.0456

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.0890

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0397

Gnomad4 FIN AF: 0.0737

Gnomad4 NFE AF: 0.0924

Gnomad4 OTH AF: 0.0860

Alfa AF: 0.0835 Hom.: 59

Bravo AF: 0.0769

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

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs35569303; hg19: chr12-12277306;