Genetic Variant APC2:p.Arg1249Pro (chr19-1467047-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005883.3(APC2):c.3746G>C(p.Arg1249Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,240 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1249H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

APC2
NM_005883.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.09

Publications

0 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 links:

C19orf25 (HGNC:26711): (chromosome 19 open reading frame 25)

C19orf25 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC2	NM_005883.3 link	c.3746G>C	p.Arg1249Pro	missense_variant	Exon 15 of 15	ENST00000590469.6	NP_005874.1	O95996-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APC2	ENST00000590469.6 link	c.3746G>C	p.Arg1249Pro	missense_variant	Exon 15 of 15	1	NM_005883.3	ENSP00000467073.2	O95996-1A0A0C4DGQ0
APC2	ENST00000233607.6 link	c.3746G>C	p.Arg1249Pro	missense_variant	Exon 15 of 15	1		ENSP00000233607.2	O95996-1
APC2	ENST00000535453.5 link	c.3746G>C	p.Arg1249Pro	missense_variant	Exon 14 of 14	1		ENSP00000442954.1	O95996-1
C19orf25	ENST00000588427.5 link	c.131-5223C>G		intron_variant	Intron 2 of 2	1		ENSP00000468000.1	K7EQW1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459240

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725888

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111572

Other (OTH)

AF:

0.0000166

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;D

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

T;.

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Pathogenic

1.1

PhyloP100

9.1

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.81

Sift

Benign

0.048

D;D

Sift4G

Uncertain

0.029

D;D

Polyphen

1.0

D;D

Vest4

0.42

MutPred

0.48

Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);

MVP

0.74

MPC

1.8

ClinPred

1.0

GERP RS

4.8

Varity_R

0.77

gMVP

0.63

Mutation Taster

=42/58

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over