rs2431507

Variant names:

• chr5-112810484-A-G
• rs2431507
• NM_000038.6:c.835-5011A>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.835-5011A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0841 in 152,296 control chromosomes in the GnomAD database, including 615 homozygotes. 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: 𝑓 0.084 (615 hom., cov: 32)
• Consequence: APC NM_000038.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.470
• Publications: 6 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: 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_000038.6	MANE Select	c.835-5011A>G		intron	N/A	NP_000029.2
	APC	NM_001407446.1		c.865-5011A>G		intron	N/A	NP_001394375.1
	APC	NM_001354896.2		c.835-5011A>G		intron	N/A	NP_001341825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.835-5011A>G		intron	N/A	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.835-5011A>G		intron	N/A	ENSP00000427089.2
	APC	ENST00000502371.3	TSL:1	n.835-5011A>G		intron	N/A	ENSP00000484935.2

Frequencies

GnomAD3 genomes AF: 0.0841 AC: 12799 AN: 152178 Hom.: 617 Cov.: 32

Gnomad AFR AF: 0.0649

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0666

Gnomad ASJ AF: 0.0677

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0936

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0808

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

GnomAD4 genome AF: 0.0841 AC: 12809 AN: 152296 Hom.: 615 Cov.: 32 AF XY: 0.0846 AC XY: 6301 AN XY: 74470

African (AFR) AF: 0.0650 AC: 2701 AN: 41560

American (AMR) AF: 0.0666 AC: 1019 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0677 AC: 235 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0935 AC: 450 AN: 4812

European-Finnish (FIN) AF: 0.104 AC: 1101 AN: 10630

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 6981 AN: 68020

Other (OTH) AF: 0.0795 AC: 168 AN: 2114

Alfa AF: 0.0959 Hom.: 118

Bravo AF: 0.0785

Asia WGS AF: 0.0340 AC: 119 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.1
DANN	Benign	0.58
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: rs2431507; hg19: chr5-112146181;