rs113534259

Variant names:

• chr19-1450086-C-T
• rs113534259
• ENST00000587869.5:c.-18-2898C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000587869.5(APC2):​c.-18-2898C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00781 in 960,586 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0056 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0082 (26 hom.)
• Consequence: APC2 ENST00000587869.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.146
• Publications: 0 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-1450086-C-T is Benign according to our data. Variant chr19-1450086-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2648922.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000587869.5. 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.-271C>T		upstream_gene	N/A	NP_005874.1	O95996-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC2	ENST00000587869.5	TSL:5	c.-18-2898C>T		intron	N/A	ENSP00000466803.2	K7EN62
	APC2	ENST00000590469.6	TSL:1 MANE Select	c.-271C>T		upstream_gene	N/A	ENSP00000467073.2	O95996-1
	APC2	ENST00000233607.6	TSL:1	c.-271C>T		upstream_gene	N/A	ENSP00000233607.2	O95996-1

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 852 AN: 152028 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00889

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00823 AC: 6651 AN: 808450 Hom.: 26 AF XY: 0.00813 AC XY: 3040 AN XY: 373998

African (AFR) AF: 0.000593 AC: 9 AN: 15168

American (AMR) AF: 0.00530 AC: 5 AN: 944

Ashkenazi Jewish (ASJ) AF: 0.00240 AC: 12 AN: 5008

East Asian (EAS) AF: 0.00 AC: 0 AN: 3504

South Asian (SAS) AF: 0.00113 AC: 18 AN: 15966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 272

Middle Eastern (MID) AF: 0.00765 AC: 12 AN: 1568

European-Non Finnish (NFE) AF: 0.00870 AC: 6432 AN: 739598

Other (OTH) AF: 0.00617 AC: 163 AN: 26422

GnomAD4 genome AF: 0.00559 AC: 850 AN: 152136 Hom.: 4 Cov.: 33 AF XY: 0.00531 AC XY: 395 AN XY: 74378

African (AFR) AF: 0.00123 AC: 51 AN: 41526

American (AMR) AF: 0.00791 AC: 121 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00255 AC: 27 AN: 10606

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00889 AC: 604 AN: 67928

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00646 Hom.: 1

Bravo AF: 0.00568

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.9
DANN	Benign	0.86
PhyloP100		0.15
PromoterAI		-0.012	Neutral

Splicing

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

Other links and lift over

dbSNP: rs113534259; hg19: chr19-1450085;