chr12-12148964-C-T

Position:

• chr12-12148964-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

LRP6 (HGNC:):

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

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP6. . Gene score misZ 2.7541 (greater than the threshold 3.09). Trascript score misZ 4.2572 (greater than threshold 3.09). GenCC has associacion of gene with coronary artery disease, autosomal dominant 2, tooth agenesis, selective, 7, tooth agenesis.
• 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP6	NM_002336.3	c.3184G>A	p.Val1062Ile	missense_variant	14/23	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.3184G>A	p.Val1062Ile	missense_variant	14/23	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.3184G>A	p.Val1062Ile	missense_variant	14/23	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.2776G>A		non_coding_transcript_exon_variant	13/24	1		ENSP00000445083.1
BCL2L14	ENST00000298566.2	n.*24+9985C>T		intron_variant		2		ENSP00000298566.1

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

GnomAD3 exomes AF: 0.851 AC: 213906 AN: 251378 Hom.: 91377 AF XY: 0.850 AC XY: 115450 AN XY: 135852

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 SAS exome AF: 0.888

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

Gnomad4 AFR exome AF: 0.870

Gnomad4 AMR exome AF: 0.921

Gnomad4 ASJ exome AF: 0.867

Gnomad4 EAS exome AF: 0.939

Gnomad4 SAS exome AF: 0.888

Gnomad4 FIN exome AF: 0.818

Gnomad4 NFE exome AF: 0.809

Gnomad4 OTH exome AF: 0.837

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

Gnomad4 AFR AF: 0.871

Gnomad4 AMR AF: 0.889

Gnomad4 ASJ AF: 0.864

Gnomad4 EAS AF: 0.931

Gnomad4 SAS AF: 0.891

Gnomad4 FIN AF: 0.812

Gnomad4 NFE AF: 0.810

Gnomad4 OTH AF: 0.853

Alfa AF: 0.824 Hom.: 108455

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.17	N
MetaRNN	Benign	0.0000086	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.2	N;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.96	N;N
REVEL	Uncertain	0.33
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2302685; hg19: chr12-12301898;