rs201709261

chr19-1457007-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005883.3(APC2):c.971C>T(p.Thr324Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,529,890 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (23 hom.)
• Consequence: APC2 NM_005883.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0370

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075882673).
• BP6: Variant 19-1457007-C-T is Benign according to our data. Variant chr19-1457007-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1457007-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC2	NM_005883.3	c.971C>T	p.Thr324Ile	missense_variant	9/15	ENST00000590469.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC2	ENST00000590469.6	c.971C>T	p.Thr324Ile	missense_variant	9/15	1	NM_005883.3	P1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 572 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00492 AC: 599 AN: 121846 Hom.: 3 AF XY: 0.00513 AC XY: 346 AN XY: 67502

Gnomad AFR exome AF: 0.00169

Gnomad AMR exome AF: 0.00432

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00400

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.00523

Gnomad OTH exome AF: 0.00960

GnomAD4 exome AF: 0.00504 AC: 6937 AN: 1377584 Hom.: 23 Cov.: 32 AF XY: 0.00512 AC XY: 3478 AN XY: 679916

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.00453

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00400

Gnomad4 FIN exome AF: 0.000672

Gnomad4 NFE exome AF: 0.00521

Gnomad4 OTH exome AF: 0.00627

GnomAD4 genome AF: 0.00376 AC: 572 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.00399 AC XY: 297 AN XY: 74468

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00484

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00608 Hom.: 0

Bravo AF: 0.00430

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00597 AC: 23

ExAC AF: 0.00234 AC: 198

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	APC2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 26, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	15
Dann	Benign	0.92
DEOGEN2	Benign	0.31	T;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.69	T;T;.;T
MetaRNN	Benign	0.0076	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.68	T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.063	.;B;B;.
Vest4		0.22, 0.23
MVP		0.36
MPC		0.63
ClinPred		0.0057	T
GERP RS		3.5
Varity_R		0.065
gMVP		0.18

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

Other links and lift over

dbSNP: rs201709261; hg19: chr19-1457006;