rs2439591

Variant names:

• chr5-112753783-T-C
• rs2439591
• NM_000038.6:c.-18-1090T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-112753783-T-C
• chr5-112753783-T-A
• chr5-112753783-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000038.6(APC):​c.-18-1090T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 152,044 control chromosomes in the GnomAD database, including 33,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: 𝑓 0.66 (33620 hom., cov: 32)
• Consequence: APC NM_000038.6 intron
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 0.465
• Publications: 12 publications found

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: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000038.6. 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
	APC	NM_000038.6	MANE Select	c.-18-1090T>C		intron	N/A	NP_000029.2
	APC	NM_001407446.1		c.166-12543T>C		intron	N/A	NP_001394375.1
	APC	NM_001354896.2		c.-18-1090T>C		intron	N/A	NP_001341825.1	R4GMU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.-18-1090T>C		intron	N/A	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.-18-1090T>C		intron	N/A	ENSP00000427089.2	P25054-1
	APC	ENST00000505084.2	TSL:1	n.39-1090T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100514 AN: 151926 Hom.: 33589 Cov.: 32

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.592

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.631

Gnomad OTH AF: 0.672

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.662 AC: 100602 AN: 152044 Hom.: 33620 Cov.: 32 AF XY: 0.661 AC XY: 49131 AN XY: 74316

African (AFR) AF: 0.709 AC: 29388 AN: 41474

American (AMR) AF: 0.708 AC: 10823 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 2053 AN: 3470

East Asian (EAS) AF: 0.796 AC: 4112 AN: 5166

South Asian (SAS) AF: 0.730 AC: 3524 AN: 4826

European-Finnish (FIN) AF: 0.538 AC: 5673 AN: 10554

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.631 AC: 42847 AN: 67950

Other (OTH) AF: 0.668 AC: 1409 AN: 2108

Alfa AF: 0.647 Hom.: 76224

Bravo AF: 0.679

Asia WGS AF: 0.755 AC: 2622 AN: 3478

ClinVar

ClinVar submissions

Significance: other

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Familial colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.5
DANN	Benign	0.76
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2439591; hg19: chr5-112089480;