rs2302685

Variant names:

• chr12-12148964-C-T
• rs2302685
• NM_002336.3:c.3184G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-12148964-C-T
• chr12-12148964-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002336.3(LRP6):​c.3184G>A​(p.Val1062Ile) variant causes a missense change. The variant allele was found at a frequency of 0.826 in 1,612,742 control chromosomes in the GnomAD database, including 551,676 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1062T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.84 (54179 hom., cov: 30)
  • Exomes 𝑓: 0.82 (497497 hom.)
• Consequence: LRP6 NM_002336.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.96
• Publications: 105 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.598283E-6).
• BP6: Variant 12-12148964-C-T is Benign according to our data. Variant chr12-12148964-C-T is described in ClinVar as Benign. ClinVar VariationId is 1575699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.909 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.3184G>A	p.Val1062Ile	missense	Exon 14 of 23	NP_002327.2	O75581
	LRP6	NM_001414244.1		c.3184G>A	p.Val1062Ile	missense	Exon 14 of 24	NP_001401173.1
	LRP6	NM_001414245.1		c.3184G>A	p.Val1062Ile	missense	Exon 14 of 24	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.3184G>A	p.Val1062Ile	missense	Exon 14 of 23	ENSP00000261349.4	O75581
	LRP6	ENST00000543091.1	TSL:1	c.3184G>A	p.Val1062Ile	missense	Exon 14 of 23	ENSP00000442472.1	F5H7J9
	LRP6	ENST00000538239.5	TSL:1	n.2776G>A		non_coding_transcript_exon	Exon 13 of 24	ENSP00000445083.1	H0YGW5

Frequencies

GnomAD3 genomes AF: 0.843 AC: 128089 AN: 151962 Hom.: 54137 Cov.: 30

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.734

Gnomad AMR AF: 0.889

Gnomad ASJ AF: 0.864

Gnomad EAS AF: 0.931

Gnomad SAS AF: 0.892

Gnomad FIN AF: 0.812

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.810

Gnomad OTH AF: 0.852

GnomAD2 exomes AF: 0.851 AC: 213906 AN: 251378 AF XY: 0.850

Gnomad AFR exome AF: 0.872

Gnomad AMR exome AF: 0.926

Gnomad ASJ exome AF: 0.867

Gnomad EAS exome AF: 0.933

Gnomad FIN exome AF: 0.819

Gnomad NFE exome AF: 0.807

Gnomad OTH exome AF: 0.838

GnomAD4 exome AF: 0.825 AC: 1204333 AN: 1460662 Hom.: 497497 Cov.: 47 AF XY: 0.826 AC XY: 600506 AN XY: 726688

African (AFR) AF: 0.870 AC: 29078 AN: 33442

American (AMR) AF: 0.921 AC: 41174 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.867 AC: 22652 AN: 26128

East Asian (EAS) AF: 0.939 AC: 37284 AN: 39696

South Asian (SAS) AF: 0.888 AC: 76536 AN: 86220

European-Finnish (FIN) AF: 0.818 AC: 43675 AN: 53414

Middle Eastern (MID) AF: 0.828 AC: 4457 AN: 5384

European-Non Finnish (NFE) AF: 0.809 AC: 898974 AN: 1111348

Other (OTH) AF: 0.837 AC: 50503 AN: 60312

GnomAD4 genome AF: 0.843 AC: 128190 AN: 152080 Hom.: 54179 Cov.: 30 AF XY: 0.846 AC XY: 62912 AN XY: 74330

African (AFR) AF: 0.871 AC: 36140 AN: 41502

American (AMR) AF: 0.889 AC: 13579 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 2998 AN: 3468

East Asian (EAS) AF: 0.931 AC: 4827 AN: 5186

South Asian (SAS) AF: 0.891 AC: 4293 AN: 4816

European-Finnish (FIN) AF: 0.812 AC: 8567 AN: 10556

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.810 AC: 55076 AN: 67968

Other (OTH) AF: 0.853 AC: 1800 AN: 2110

Alfa AF: 0.827 Hom.: 154843

Bravo AF: 0.849

TwinsUK AF: 0.801 AC: 2970

ALSPAC AF: 0.806 AC: 3105

ESP6500AA AF: 0.874 AC: 3853

ESP6500EA AF: 0.822 AC: 7072

ExAC AF: 0.847 AC: 102882

Asia WGS AF: 0.907 AC: 3154 AN: 3478

EpiCase AF: 0.809

EpiControl AF: 0.815

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.17	N
MetaRNN	Benign	0.0000086	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.2	N
PhyloP100		6.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.96	N
REVEL	Uncertain	0.33
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.14
MPC		0.42
ClinPred		0.026	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.14
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2302685; hg19: chr12-12301898; COSMIC: COSV107206867;