chr19-1457007-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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. 13/20 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0370

Publications

2 publications found

Variant links:

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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
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)

APC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/Likely_benign. Clinvar id is 445326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 23 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC2	NM_005883.3 link	c.971C>T	p.Thr324Ile	missense_variant	Exon 9 of 15	ENST00000590469.6	NP_005874.1	O95996-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC2	ENST00000590469.6 link	c.971C>T	p.Thr324Ile	missense_variant	Exon 9 of 15	1	NM_005883.3	ENSP00000467073.2		O95996-1A0A0C4DGQ0

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

572

AN:

152192

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00492

AC:

599

AN:

121846

AF XY:

0.00513

show subpopulations

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 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.:

Cov.:

AF XY:

0.00512

AC XY:

3478

AN XY:

679916

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

30062

American (AMR)

AF:

0.00453

AC:

157

AN:

34694

Ashkenazi Jewish (ASJ)

AF:

0.0155

AC:

385

AN:

24840

East Asian (EAS)

AF:

0.00

AC:

AN:

34644

South Asian (SAS)

AF:

0.00400

AC:

313

AN:

78342

European-Finnish (FIN)

AF:

0.000672

AC:

AN:

35730

Middle Eastern (MID)

AF:

0.0100

AC:

AN:

5288

European-Non Finnish (NFE)

AF:

0.00521

AC:

5611

AN:

1076522

Other (OTH)

AF:

0.00627

AC:

360

AN:

57462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

496

993

1489

1986

2482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

218

436

654

872

1090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00376

AC:

572

AN:

152306

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

297

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41564

American (AMR)

AF:

0.00621

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00248

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00484

AC:

329

AN:

68010

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00564

Hom.:

Bravo

AF:

0.00430

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00597

AC:

ExAC

AF:

0.00234

AC:

198

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

APC2: BS2 -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 26, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

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

LIST_S2

Benign

0.69

T;T;.;T

MetaRNN

Benign

0.0076

T;T;T;T

MetaSVM

Benign

-0.99

PhyloP100

0.037

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.8

.;D;D;.

REVEL

Benign

0.086

Sift

Benign

0.074

.;T;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

GERP RS

3.5

Varity_R

0.065

gMVP

0.18

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over