rs11054738

chr12-12235093-T-Achr12-12235093-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002336.3(LRP6):c.449+9169A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,132 control chromosomes in the GnomAD database, including 1,895 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 0.15 (1895 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.382

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP6	NM_002336.3	c.449+9169A>T		intron_variant		ENST00000261349.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP6	ENST00000261349.9	c.449+9169A>T		intron_variant		1	NM_002336.3	P1
LRP6	ENST00000543091.1	c.449+9169A>T		intron_variant		1
LRP6	ENST00000538239.5	c.43+9169A>T		intron_variant, NMD_transcript_variant		1
LRP6	ENST00000535731.1	c.-5+31588A>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22684 AN: 152012 Hom.: 1895 Cov.: 32

Gnomad AFR AF: 0.0993

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.0505

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.143

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

GnomAD4 genome AF: 0.149 AC: 22695 AN: 152132 Hom.: 1895 Cov.: 32 AF XY: 0.146 AC XY: 10889 AN XY: 74374

Gnomad4 AFR AF: 0.0993

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.0506

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.191

Gnomad4 NFE AF: 0.190

Gnomad4 OTH AF: 0.142

Alfa AF: 0.102 Hom.: 159

Bravo AF: 0.141

Asia WGS AF: 0.0870 AC: 303 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	7.9
Dann	Benign	0.72

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: rs11054738; hg19: chr12-12388027;