12-12175830-T-C

Variant names:

• chr12-12175830-T-C
• rs7305037
• NM_002336.3:c.1545+3980A>G

Variant summary

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

The NM_001414244.1(LRP6):​c.1545+3980A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 151,532 control chromosomes in the GnomAD database, including 14,327 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 0.39 (14327 hom., cov: 33)
• Consequence: LRP6 NM_001414244.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0130
• Publications: 3 publications found

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001414244.1. 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
	LRP6	NM_002336.3	MANE Select	c.1545+3980A>G		intron	N/A	NP_002327.2
	LRP6	NM_001414244.1		c.1545+3980A>G		intron	N/A	NP_001401173.1
	LRP6	NM_001414245.1		c.1545+3980A>G		intron	N/A	NP_001401174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	ENST00000261349.9	TSL:1 MANE Select	c.1545+3980A>G		intron	N/A	ENSP00000261349.4
	LRP6	ENST00000543091.1	TSL:1	c.1545+3980A>G		intron	N/A	ENSP00000442472.1
	LRP6	ENST00000538239.5	TSL:1	n.1137+3980A>G		intron	N/A	ENSP00000445083.1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59838 AN: 151414 Hom.: 14340 Cov.: 33

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.634

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.412

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

GnomAD4 genome AF: 0.395 AC: 59831 AN: 151532 Hom.: 14327 Cov.: 33 AF XY: 0.409 AC XY: 30288 AN XY: 74070

African (AFR) AF: 0.120 AC: 4998 AN: 41506

American (AMR) AF: 0.502 AC: 7648 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1542 AN: 3466

East Asian (EAS) AF: 0.721 AC: 3735 AN: 5178

South Asian (SAS) AF: 0.632 AC: 3047 AN: 4822

European-Finnish (FIN) AF: 0.553 AC: 5627 AN: 10174

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.470 AC: 31906 AN: 67824

Other (OTH) AF: 0.415 AC: 874 AN: 2108

Alfa AF: 0.416 Hom.: 1778

Bravo AF: 0.376

Asia WGS AF: 0.638 AC: 2209 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.2
DANN	Benign	0.76
PhyloP100		-0.013
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: rs7305037; hg19: chr12-12328764;