rs13377971

Variant names:

• chr12-12127376-G-A
• rs13377971
• NM_002336.3:c.4082-455C>T

Variant summary

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

The NM_002336.3(LRP6):​c.4082-455C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0723 in 152,236 control chromosomes in the GnomAD database, including 527 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 0.072 (527 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.336
• 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=-0.71).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002336.3. 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.4082-455C>T		intron	N/A	NP_002327.2	O75581
	LRP6	NM_001414244.1		c.4175-455C>T		intron	N/A	NP_001401173.1
	LRP6	NM_001414245.1		c.4082-455C>T		intron	N/A	NP_001401174.1	O75581

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	ENST00000261349.9	TSL:1 MANE Select	c.4082-455C>T		intron	N/A	ENSP00000261349.4	O75581
	LRP6	ENST00000543091.1	TSL:1	c.3947-455C>T		intron	N/A	ENSP00000442472.1	F5H7J9
	LRP6	ENST00000538239.5	TSL:1	n.3674-455C>T		intron	N/A	ENSP00000445083.1	H0YGW5

Frequencies

GnomAD3 genomes AF: 0.0723 AC: 11005 AN: 152118 Hom.: 527 Cov.: 32

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0882

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.0750

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0996

Gnomad OTH AF: 0.0850

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

GnomAD4 genome AF: 0.0723 AC: 11004 AN: 152236 Hom.: 527 Cov.: 32 AF XY: 0.0715 AC XY: 5324 AN XY: 74432

African (AFR) AF: 0.0232 AC: 965 AN: 41552

American (AMR) AF: 0.111 AC: 1694 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0882 AC: 306 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5192

South Asian (SAS) AF: 0.0396 AC: 191 AN: 4824

European-Finnish (FIN) AF: 0.0750 AC: 794 AN: 10592

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0995 AC: 6769 AN: 67996

Other (OTH) AF: 0.0841 AC: 178 AN: 2116

Alfa AF: 0.0829 Hom.: 71

Bravo AF: 0.0732

Asia WGS AF: 0.0190 AC: 65 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.1
DANN	Benign	0.73
PhyloP100		-0.34
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: rs13377971; hg19: chr12-12280310;