rs869320641

Positions:

• chr12-12181412-C-A
• chr12-12181412-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM1 PM2 PP2 PP3_Moderate BS2

The NM_002336.3(LRP6):​c.1004G>T​(p.Arg335Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000401 in 1,246,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: LRP6 NM_002336.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a region_of_interest Beta-propeller 2 (size 261) in uniprot entity LRP6_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_002336.3
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP6	NM_002336.3	c.1004G>T	p.Arg335Leu	missense_variant	6/23	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.1004G>T	p.Arg335Leu	missense_variant	6/23	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.1004G>T	p.Arg335Leu	missense_variant	6/23	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.596G>T		non_coding_transcript_exon_variant	5/24	1		ENSP00000445083.1
BCL2L14	ENST00000298566.2	n.*25-5893C>A		intron_variant		2		ENSP00000298566.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000401 AC: 5 AN: 1246640 Hom.: 0 Cov.: 22 AF XY: 0.00000158 AC XY: 1 AN XY: 631124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000545

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000337 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Orofacial cleft Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Mar 10, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.99	D;D
Vest4		0.79
MVP		0.89
MPC		1.6
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.56
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs869320641; hg19: chr12-12334346;