19-1453018-C-A

Variant names:

• chr19-1453018-C-A
• NM_005883.3:c.17C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005883.3(APC2):​c.17C>A​(p.Ala6Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,944 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: APC2 NM_005883.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38585824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC2	NM_005883.3	c.17C>A	p.Ala6Glu	missense_variant	Exon 2 of 15	ENST00000590469.6	NP_005874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC2	ENST00000590469.6	c.17C>A	p.Ala6Glu	missense_variant	Exon 2 of 15	1	NM_005883.3	ENSP00000467073.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458944 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;T;T;T;T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T;T;T;.;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.7	.;.;.;D;D;.;D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	.;.;.;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;D;.;.
Vest4		0.72, 0.50
MutPred		0.11		Gain of phosphorylation at S3 (P = 0.1152);Gain of phosphorylation at S3 (P = 0.1152);Gain of phosphorylation at S3 (P = 0.1152);Gain of phosphorylation at S3 (P = 0.1152);Gain of phosphorylation at S3 (P = 0.1152);Gain of phosphorylation at S3 (P = 0.1152);Gain of phosphorylation at S3 (P = 0.1152);
MVP		0.40
MPC		1.6
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.79
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-1453017;