rs16907810

Variant names:

• chr12-12174721-T-C
• rs16907810
• NM_002336.3:c.1545+5089A>G

Variant summary

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

The NM_002336.3(LRP6):​c.1545+5089A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 152,164 control chromosomes in the GnomAD database, including 3,075 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 0.20 (3075 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.126
• Publications: 6 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=-0.61).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.1545+5089A>G		intron_variant	Intron 7 of 22	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.1545+5089A>G		intron_variant	Intron 7 of 22	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.1545+5089A>G		intron_variant	Intron 7 of 22	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.1137+5089A>G		intron_variant	Intron 6 of 23	1		ENSP00000445083.1
BCL2L14	ENST00000298566.2	n.*25-12584T>C		intron_variant	Intron 5 of 6	2		ENSP00000298566.1

Frequencies

GnomAD3 genomes AF: 0.197 AC: 30024 AN: 152044 Hom.: 3074 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.192

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

GnomAD4 genome AF: 0.197 AC: 30050 AN: 152164 Hom.: 3075 Cov.: 32 AF XY: 0.192 AC XY: 14287 AN XY: 74414

African (AFR) AF: 0.237 AC: 9838 AN: 41502

American (AMR) AF: 0.188 AC: 2876 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 807 AN: 3470

East Asian (EAS) AF: 0.177 AC: 918 AN: 5184

South Asian (SAS) AF: 0.205 AC: 987 AN: 4826

European-Finnish (FIN) AF: 0.125 AC: 1322 AN: 10608

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12656 AN: 67978

Other (OTH) AF: 0.193 AC: 406 AN: 2106

Alfa AF: 0.193 Hom.: 3814

Bravo AF: 0.204

Asia WGS AF: 0.190 AC: 661 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.4
DANN	Benign	0.62
PhyloP100		-0.13
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: rs16907810; hg19: chr12-12327655; COSMIC: COSV53795887;