Genetic Variant APC:c.-307C>G (chr5-112707411-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001407446.1(APC):c.-307C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 235,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

APC
NM_001407446.1 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.861

Publications

0 publications found

Variant links:

Genes affected

APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

APC Gene-Disease associations (from GenCC):

classic or attenuated familial adenomatous polyposis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
desmoid tumor
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
familial adenomatous polyposis 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
gastric adenocarcinoma and proximal polyposis of the stomach
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
APC-related attenuated familial adenomatous polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Turcot syndrome with polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cenani-Lenz syndactyly syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

APC links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Protein
APC	NM_001407446.1 link	c.-307C>G	upstream_gene_variant	NP_001394375.1
APC	NM_001407447.1 link	c.-490C>G	upstream_gene_variant	NP_001394376.1
APC	NM_001407448.1 link	c.-257C>G	upstream_gene_variant	NP_001394377.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	Protein	UniProt
APC	ENST00000509732.6 link	c.-257C>G	upstream_gene_variant	4	ENSP00000426541.2	D6RFL6
APC	ENST00000507379.6 link	c.-307C>G	upstream_gene_variant	2	ENSP00000423224.2	A0A2Q2SV78
APC	ENST00000505350.2 link	n.-307C>G	upstream_gene_variant	3	ENSP00000481752.1	A0A087WYF3
APC	ENST00000713636.1 link	n.-490C>G	upstream_gene_variant		ENSP00000518937.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000425

AC:

AN:

235438

Hom.:

AF XY:

0.00000826

AC XY:

AN XY:

121048

show subpopulations

African (AFR)

AF:

0.000127

AC:

AN:

7890

American (AMR)

AF:

0.00

AC:

AN:

10776

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8382

East Asian (EAS)

AF:

0.00

AC:

AN:

17256

South Asian (SAS)

AF:

0.00

AC:

AN:

33486

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1052

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

134478

Other (OTH)

AF:

0.00

AC:

AN:

14194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.5

(source)

DANN

Benign

0.48

PhyloP100

-0.86

PromoterAI

0.018

Neutral

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over