rs867728580

Variant names:

• chr19-1453305-C-A
• rs867728580
• NM_005883.3:c.200C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1453305-C-A
• chr19-1453305-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.40
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• cortical dysplasia, complex, with other brain malformations 10

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
• lissencephaly spectrum disorders

  Inheritance: AR Classification: STRONG Submitted by: ClinGen
• Sotos syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual developmental disorder, autosomal recessive 74

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005883.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC2	NM_005883.3	MANE Select	c.200C>A	p.Ser67*	stop_gained	Exon 3 of 15	NP_005874.1	O95996-1
	APC2	NM_001351273.1		c.200C>A	p.Ser67*	stop_gained	Exon 2 of 14	NP_001338202.1	O95996-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC2	ENST00000590469.6	TSL:1 MANE Select	c.200C>A	p.Ser67*	stop_gained	Exon 3 of 15	ENSP00000467073.2	O95996-1
	APC2	ENST00000233607.6	TSL:1	c.200C>A	p.Ser67*	stop_gained	Exon 3 of 15	ENSP00000233607.2	O95996-1
	APC2	ENST00000535453.5	TSL:1	c.200C>A	p.Ser67*	stop_gained	Exon 2 of 14	ENSP00000442954.1	O95996-1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33198

American (AMR) AF: 0.0000251 AC: 1 AN: 39834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25646

East Asian (EAS) AF: 0.00 AC: 0 AN: 38832

South Asian (SAS) AF: 0.00 AC: 0 AN: 84184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100814

Other (OTH) AF: 0.00 AC: 0 AN: 59546

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.4
Vest4		0.74
GERP RS		3.8
Mutation Taster		=15/185	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs867728580; hg19: chr19-1453304;