chr19-1462030-C-T

Position:

chr19-1462030-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005883.3(APC2):c.1706C>T(p.Ala569Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

APC2
NM_005883.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.71

Variant links:

Genes affected

APC2 (HGNC:24036): (APC regulator of WNT signaling pathway 2) This gene encodes a strongly conserved protein that has an N-terminal coiled-coil domain followed by an armadillo domain, five 20-amino acid repeats, and two SAMP domains. This protein promotes the assembly of a multiprotein complex that recruits and phosphorylates the Wnt effector beta-catenin and targets beta-catenin for ubiquitylation and proteasomal degradation. This protein therefore plays a role in the reduction of cytoplasmic levels of beta-catenin which in turn reduces activation of Wnt target genes that play a pivotal role in the pathogenesis of various human cancers. The protein encoded by this gene is closely related to the adenomatous polyposis coli (APC) tumor-suppressor protein and has similar tumor-suppressor effects. This gene also plays a role in actin assembly, cell-cell adhesion, and microtubule network formation through its interaction with cytoskeletal proteins. This gene has its highest expression in the central nervous system and is involved in brain development through cytoskeletal regulation in neurons. Alternative splicing produces multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2017]

APC2 links:

C19orf25 (HGNC:26711): (chromosome 19 open reading frame 25)

C19orf25 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16542536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC2	NM_005883.3 linkuse as main transcript	c.1706C>T	p.Ala569Val	missense_variant	14/15	ENST00000590469.6	NP_005874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC2	ENST00000590469.6 linkuse as main transcript	c.1706C>T	p.Ala569Val	missense_variant	14/15	1	NM_005883.3	ENSP00000467073	P1	O95996-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000678

AC:

AN:

250560

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1460900

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726754

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with APC2-related conditions. This variant is present in population databases (rs777444839, gnomAD 0.04%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 569 of the APC2 protein (p.Ala569Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

T;T;T;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.91

D;D;.;D

M_CAP

Benign

0.055

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Benign

-0.90

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.6

.;D;D;.

REVEL

Benign

0.21

Sift

Benign

0.18

.;T;T;.

Sift4G

Benign

0.46

T;T;T;T

Polyphen

0.97

.;D;D;.

Vest4

0.55, 0.59

MutPred

0.29

Loss of ubiquitination at K568 (P = 0.0509);Loss of ubiquitination at K568 (P = 0.0509);Loss of ubiquitination at K568 (P = 0.0509);.;

MVP

0.45

MPC

0.64

ClinPred

0.19

GERP RS

4.6

Varity_R

0.33

gMVP

0.26

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over