chr20-33629720-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001032999.3(CBFA2T2):​c.1034C>T​(p.Ala345Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,611,322 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 1 hom. )

Consequence

CBFA2T2
NM_001032999.3 missense, splice_region

Scores

4
15
Splicing: ADA: 0.09776
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.33
Variant links:
Genes affected
CBFA2T2 (HGNC:1536): (CBFA2/RUNX1 partner transcriptional co-repressor 2) In acute myeloid leukemia, especially in the M2 subtype, the t(8;21)(q22;q22) translocation is one of the most frequent karyotypic abnormalities. The translocation produces a chimeric gene made up of the 5'-region of the RUNX1 (AML1) gene fused to the 3'-region of the CBFA2T1 (MTG8) gene. The chimeric protein is thought to associate with the nuclear corepressor/histone deacetylase complex to block hematopoietic differentiation. The protein encoded by this gene binds to the AML1-MTG8 complex and may be important in promoting leukemogenesis. Several transcript variants are thought to exist for this gene, but the full-length natures of only three have been described. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.042965382).
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CBFA2T2NM_001032999.3 linkc.1034C>T p.Ala345Val missense_variant, splice_region_variant Exon 8 of 11 ENST00000342704.11 NP_001028171.1 O43439-5
CBFA2T2NM_005093.4 linkc.1061C>T p.Ala354Val missense_variant, splice_region_variant Exon 9 of 12 NP_005084.1 O43439-1
CBFA2T2NM_001039709.2 linkc.974C>T p.Ala325Val missense_variant, splice_region_variant Exon 8 of 11 NP_001034798.1 O43439-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CBFA2T2ENST00000342704.11 linkc.1034C>T p.Ala345Val missense_variant, splice_region_variant Exon 8 of 11 1 NM_001032999.3 ENSP00000345810.6 O43439-5

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000962
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000105
AC:
26
AN:
248668
Hom.:
0
AF XY:
0.0000892
AC XY:
12
AN XY:
134454
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00136
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000889
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1459060
Hom.:
1
Cov.:
30
AF XY:
0.0000276
AC XY:
20
AN XY:
725924
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000580
Gnomad4 SAS exome
AF:
0.0000349
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000810
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152262
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000965
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000416
ExAC
AF:
0.0000906
AC:
11

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 07, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1061C>T (p.A354V) alteration is located in exon 9 (coding exon 8) of the CBFA2T2 gene. This alteration results from a C to T substitution at nucleotide position 1061, causing the alanine (A) at amino acid position 354 to be replaced by a valine (V). 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
0.24
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.48
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
.;T;T;.;.;.
Eigen
Benign
-0.14
Eigen_PC
Benign
0.012
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.89
D;.;D;D;.;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.043
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.69
.;N;N;.;.;.
PrimateAI
Uncertain
0.79
T
PROVEAN
Benign
1.5
N;N;N;N;N;N
REVEL
Benign
0.12
Sift
Benign
0.14
T;T;T;T;T;T
Sift4G
Benign
0.32
T;T;T;T;T;T
Polyphen
0.65
.;P;P;.;.;.
Vest4
0.26
MutPred
0.53
.;Loss of ubiquitination at K349 (P = 0.1037);Loss of ubiquitination at K349 (P = 0.1037);.;.;.;
MVP
0.16
MPC
0.65
ClinPred
0.089
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.13
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.098
dbscSNV1_RF
Benign
0.23
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs568783051; hg19: chr20-32217526; API