dbSNP rs2302685: LRP6:p.Val1062Leu (chr12-12148964-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002336.3(LRP6):c.3184G>C(p.Val1062Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1062I) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LRP6
NM_002336.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.96

Publications

0 publications found

Variant links:

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 links:

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]

BCL2L14 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30850837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3 link	c.3184G>C	p.Val1062Leu	missense_variant	Exon 14 of 23	ENST00000261349.9	NP_002327.2	O75581

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRP6	ENST00000261349.9 link	c.3184G>C	p.Val1062Leu	missense_variant	Exon 14 of 23	1	NM_002336.3	ENSP00000261349.4	O75581
LRP6	ENST00000543091.1 link	c.3184G>C	p.Val1062Leu	missense_variant	Exon 14 of 23	1		ENSP00000442472.1	F5H7J9
LRP6	ENST00000538239.5 link	n.2776G>C		non_coding_transcript_exon_variant	Exon 13 of 24	1		ENSP00000445083.1	H0YGW5
BCL2L14	ENST00000298566.2 link	n.*24+9985C>G		intron_variant	Intron 5 of 6	2		ENSP00000298566.1	Q9BZR8-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461178

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726924

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5388

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111806

Other (OTH)

AF:

0.00

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.00080

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.075

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

-0.64

N;.

PhyloP100

6.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.060

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.30

T;T

Sift4G

Benign

0.41

T;T

Polyphen

0.0

B;B

Vest4

0.27

MutPred

0.80

Gain of relative solvent accessibility (P = 0.2363);Gain of relative solvent accessibility (P = 0.2363);

MVP

0.38

MPC

0.51

ClinPred

0.70

GERP RS

5.5

Varity_R

0.14

gMVP

0.41

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over