rs141982003

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004380.3(CREBBP):​c.293G>T​(p.Gly98Val) variant causes a missense change. The variant allele was found at a frequency of 0.000387 in 1,614,108 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 30)
Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

CREBBP
NM_004380.3 missense

Scores

1
11
6

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 5.70
Variant links:
Genes affected
CREBBP (HGNC:2348): (CREB binding protein) This gene is ubiquitously expressed and is involved in the transcriptional coactivation of many different transcription factors. First isolated as a nuclear protein that binds to cAMP-response element binding protein (CREB), this gene is now known to play critical roles in embryonic development, growth control, and homeostasis by coupling chromatin remodeling to transcription factor recognition. The protein encoded by this gene has intrinsic histone acetyltransferase activity and also acts as a scaffold to stabilize additional protein interactions with the transcription complex. This protein acetylates both histone and non-histone proteins. This protein shares regions of very high sequence similarity with protein p300 in its bromodomain, cysteine-histidine-rich regions, and histone acetyltransferase domain. Mutations in this gene cause Rubinstein-Taybi syndrome (RTS). Chromosomal translocations involving this gene have been associated with acute myeloid leukemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CREBBP. . Gene score misZ 3.8991 (greater than the threshold 3.09). Trascript score misZ 4.7573 (greater than threshold 3.09). GenCC has associacion of gene with Menke-Hennekam syndrome 1, Rubinstein-Taybi syndrome due to CREBBP mutations, Rubinstein-Taybi syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.008755326).
BP6
Variant 16-3850802-C-A is Benign according to our data. Variant chr16-3850802-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 133932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00193 (294/152306) while in subpopulation AFR AF= 0.00676 (281/41568). AF 95% confidence interval is 0.00611. There are 2 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
High AC in GnomAd4 at 294 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CREBBPNM_004380.3 linkuse as main transcriptc.293G>T p.Gly98Val missense_variant 2/31 ENST00000262367.10 NP_004371.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CREBBPENST00000262367.10 linkuse as main transcriptc.293G>T p.Gly98Val missense_variant 2/311 NM_004380.3 ENSP00000262367 P1Q92793-1
CREBBPENST00000382070.7 linkuse as main transcriptc.293G>T p.Gly98Val missense_variant 2/301 ENSP00000371502 Q92793-2

Frequencies

GnomAD3 genomes
AF:
0.00193
AC:
293
AN:
152188
Hom.:
2
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00676
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000521
AC:
131
AN:
251230
Hom.:
0
AF XY:
0.000353
AC XY:
48
AN XY:
135816
show subpopulations
Gnomad AFR exome
AF:
0.00776
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000226
AC:
330
AN:
1461802
Hom.:
0
Cov.:
32
AF XY:
0.000201
AC XY:
146
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.00827
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.000596
GnomAD4 genome
AF:
0.00193
AC:
294
AN:
152306
Hom.:
2
Cov.:
30
AF XY:
0.00172
AC XY:
128
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.00676
Gnomad4 AMR
AF:
0.000457
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000333
Hom.:
2
Bravo
AF:
0.00219
ESP6500AA
AF:
0.00842
AC:
37
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000692
AC:
84
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2024CREBBP: BS1 -
Benign, criteria provided, single submitterclinical testingGeneDxFeb 19, 2020- -
not specified Benign:1Other:1
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 19, 2016- -
not provided, no classification providedreference populationITMISep 19, 2013- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 06, 2016This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Rubinstein-Taybi syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.099
T
BayesDel_noAF
Uncertain
0.090
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.55
D;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;D
MetaRNN
Benign
0.0088
T;T
MetaSVM
Uncertain
0.33
D
MutationAssessor
Benign
1.2
L;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-2.5
D;N
REVEL
Uncertain
0.64
Sift
Uncertain
0.022
D;D
Sift4G
Benign
0.12
T;T
Polyphen
1.0
D;.
Vest4
0.69
MVP
0.86
MPC
0.70
ClinPred
0.069
T
GERP RS
4.9
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.8
Varity_R
0.40
gMVP
0.38

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

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

Other links and lift over

dbSNP: rs141982003; hg19: chr16-3900803; API