16-3770722-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004380.3(CREBBP):c.2728A>G(p.Thr910Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,613,886 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T910S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2 B:13
• Conservation: PhyloP100: 1.43

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CREBBP
• BP4: Computational evidence support a benign effect (MetaRNN=0.005923271).
• BP6: Variant 16-3770722-T-C is Benign according to our data. Variant chr16-3770722-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 30042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3770722-T-C is described in Lovd as [Benign]. Variant chr16-3770722-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00232 (353/152042) while in subpopulation NFE AF= 0.00315 (214/67968). AF 95% confidence interval is 0.0028. There are 0 homozygotes in gnomad4. There are 199 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 353 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.2728A>G	p.Thr910Ala	missense_variant	14/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.2728A>G	p.Thr910Ala	missense_variant	14/31	1	NM_004380.3	P1
CREBBP	ENST00000382070.7	c.2614A>G	p.Thr872Ala	missense_variant	13/30	1
CREBBP	ENST00000570939.2	c.1333A>G	p.Thr445Ala	missense_variant	9/23	5
CREBBP	ENST00000573672.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 151926 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00240 AC: 603 AN: 251324 Hom.: 2 AF XY: 0.00226 AC XY: 307 AN XY: 135840

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00953

Gnomad NFE exome AF: 0.00311

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00239 AC: 3487 AN: 1461844 Hom.: 9 Cov.: 33 AF XY: 0.00239 AC XY: 1739 AN XY: 727218

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00923

Gnomad4 NFE exome AF: 0.00249

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152042 Hom.: 0 Cov.: 31 AF XY: 0.00268 AC XY: 199 AN XY: 74324

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0109

Gnomad4 NFE AF: 0.00315

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00263 Hom.: 3

Bravo AF: 0.00144

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00233 AC: 283

EpiCase AF: 0.00234

EpiControl AF: 0.00213

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2 Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2019	This variant is associated with the following publications: (PMID: 20684013) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CREBBP: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 01, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 15, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Tip-toe gait Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Apr 04, 2022

- -

Rubinstein-Taybi syndrome due to CREBBP mutations Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2010

- -

CREBBP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2018

This alteration is classified as likely 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 submitter

clinical testing

Invitae

Jan 31, 2024

- -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	13
Dann	Benign	0.82
DEOGEN2	Benign	0.34	T;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.46	T;T;T
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.0	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.55	N;N;.
REVEL	Benign	0.14
Sift	Benign	0.71	T;T;.
Sift4G	Benign	0.77	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.086
MVP		0.59
MPC		0.087
ClinPred		0.00086	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.081

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143247685; hg19: chr16-3820723; COSMIC: COSV52120594; COSMIC: COSV52120594;