19-1468494-GCCC-GCCCC
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_005883.3(APC2):c.5199dup(p.Lys1734GlnfsTer419) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,604 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
APC2
NM_005883.3 frameshift
NM_005883.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.05
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-1468494-G-GC is Pathogenic according to our data. Variant chr19-1468494-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 267259.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC2 | NM_005883.3 | c.5199dup | p.Lys1734GlnfsTer419 | frameshift_variant | 15/15 | ENST00000590469.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC2 | ENST00000590469.6 | c.5199dup | p.Lys1734GlnfsTer419 | frameshift_variant | 15/15 | 1 | NM_005883.3 | P1 | |
APC2 | ENST00000233607.6 | c.5199dup | p.Lys1734GlnfsTer419 | frameshift_variant | 15/15 | 1 | P1 | ||
APC2 | ENST00000535453.5 | c.5199dup | p.Lys1734GlnfsTer419 | frameshift_variant | 14/14 | 1 | P1 | ||
C19orf25 | ENST00000588427.5 | c.131-6671_131-6670insG | intron_variant | 1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1452604Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1AN XY: 721998
GnomAD4 exome
AF:
AC:
2
AN:
1452604
Hom.:
Cov.:
34
AF XY:
AC XY:
1
AN XY:
721998
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Intellectual developmental disorder, autosomal recessive 74 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 02, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at