19-1453305-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_005883.3(APC2):​c.200C>A​(p.Ser67*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

APC2
NM_005883.3 stop_gained

Scores

2
4
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.40
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APC2NM_005883.3 linkc.200C>A p.Ser67* stop_gained Exon 3 of 15 ENST00000590469.6 NP_005874.1 O95996-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APC2ENST00000590469.6 linkc.200C>A p.Ser67* stop_gained Exon 3 of 15 1 NM_005883.3 ENSP00000467073.2 O95996-1A0A0C4DGQ0

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.95e-7
AC:
1
AN:
1438774
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
713766
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000251
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.87
D
Vest4
0.74, 0.74
GERP RS
3.8

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.

Other links and lift over

dbSNP: rs867728580; hg19: chr19-1453304; API