chr5-112766336-A-G

Position:

• chr5-112766336-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000038.6(APC):​c.146A>G​(p.Lys49Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.09

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.418405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.146A>G	p.Lys49Arg	missense_variant	3/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.146A>G	p.Lys49Arg	missense_variant	3/16	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2013

​The p.K49R variant (also known as c.146A>G) is located in coding exon 2 of the APC gene. This alteration results from a A to G substitution at nucleotide position 146. The lysine at codon 49 is replaced by arginine, an amino acid with highly similar properties. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 6000 alleles tested) in our clinical cohort (includes this individual). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damging, but tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.I391V remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;D;D;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.42	T;T;T;T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.7	.;.;L;L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.2	N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.063	T;D;T;T;D
Sift4G	Pathogenic	0.0	D;T;T;T;T
Polyphen		1.0	.;.;D;D;.
Vest4		0.68, 0.73
MutPred		0.20		Loss of ubiquitination at K49 (P = 0.0019);.;Loss of ubiquitination at K49 (P = 0.0019);Loss of ubiquitination at K49 (P = 0.0019);Loss of ubiquitination at K49 (P = 0.0019);
MVP		0.91
ClinPred		0.87	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs587781587; hg19: chr5-112102033;