rs2546108

Positions:

• chr5-112825772-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000038.6(APC):​c.1409-1336C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 152,102 control chromosomes in the GnomAD database, including 14,705 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: 𝑓 0.40 (14705 hom., cov: 32)
• Consequence: APC NM_000038.6 intron
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 0.303

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.1409-1336C>A		intron_variant		ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1409-1336C>A		intron_variant		5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61396 AN: 151984 Hom.: 14708 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.665

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.437

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

GnomAD4 genome AF: 0.404 AC: 61400 AN: 152102 Hom.: 14705 Cov.: 32 AF XY: 0.407 AC XY: 30270 AN XY: 74344

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.560

Gnomad4 ASJ AF: 0.480

Gnomad4 EAS AF: 0.664

Gnomad4 SAS AF: 0.552

Gnomad4 FIN AF: 0.411

Gnomad4 NFE AF: 0.491

Gnomad4 OTH AF: 0.436

Alfa AF: 0.451 Hom.: 5788

Bravo AF: 0.406

Asia WGS AF: 0.562 AC: 1953 AN: 3478

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial colorectal cancer Other:1

other, no assertion criteria provided

literature only

Systems Biology Platform Zhejiang California International NanoSystems Institute

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.0
DANN	Benign	0.71

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

LitVar

Other links and lift over

dbSNP: rs2546108; hg19: chr5-112161469;