22-38671072-A-G

Position:

• chr22-38671072-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015373.4(CBY1):​c.187A>G​(p.Thr63Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CBY1 NM_015373.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0600

Genes affected

CBY1 (HGNC:1307): (chibby 1, beta catenin antagonist) Beta-catenin is a transcriptional activator and oncoprotein involved in the development of several cancers. The protein encoded by this gene interacts directly with the C-terminal region of beta-catenin, inhibiting oncogenic beta-catenin-mediated transcriptional activation by competing with transcription factors for binding to beta-catenin. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TOMM22-DT (HGNC:56758): (TOMM22 divergent transcript)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051936895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBY1	NM_015373.4	c.187A>G	p.Thr63Ala	missense_variant, splice_region_variant	4/5	ENST00000216029.8	NP_056188.1
CBY1	NM_001002880.4	c.187A>G	p.Thr63Ala	missense_variant, splice_region_variant	5/6		NP_001002880.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBY1	ENST00000216029.8	c.187A>G	p.Thr63Ala	missense_variant, splice_region_variant	4/5	1	NM_015373.4	ENSP00000216029	P1
TOMM22-DT	ENST00000431924.3	n.136-2747T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2024

The c.316A>G (p.T106A) alteration is located in exon 6 (coding exon 4) of the CBY1 gene. This alteration results from a A to G substitution at nucleotide position 316, causing the threonine (T) at amino acid position 106 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.17	T;T;.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.58	.;T;T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.052	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N;N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.050	N;N;N;.
REVEL	Benign	0.029
Sift	Benign	0.24	T;T;T;.
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.12
MutPred		0.24		Gain of catalytic residue at T63 (P = 0.0236);Gain of catalytic residue at T63 (P = 0.0236);Gain of catalytic residue at T63 (P = 0.0236);.;
MVP		0.26
MPC		0.23
ClinPred		0.12	T
GERP RS		-1.6
Varity_R		0.029
gMVP		0.078

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-39067077;