rs142047649

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP6_Very_StrongBS1BS2

The NM_004380.3(CREBBP):c.2678C>T(p.Ser893Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,614,080 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts 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. S893W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0021 ( 9 hom. )

Consequence

CREBBP
NM_004380.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 8.93

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]

CREBBP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant where missense usually causes diseases, CREBBP

BP6

Variant 16-3770772-G-A is Benign according to our data. Variant chr16-3770772-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3770772-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00135 (206/152204) while in subpopulation NFE AF= 0.0019 (129/67996). AF 95% confidence interval is 0.00163. There are 2 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd at 206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3 linkuse as main transcript	c.2678C>T	p.Ser893Leu	missense_variant	14/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10 linkuse as main transcript	c.2678C>T	p.Ser893Leu	missense_variant	14/31	1	NM_004380.3	P1	Q92793-1
CREBBP	ENST00000382070.7 linkuse as main transcript	c.2564C>T	p.Ser855Leu	missense_variant	13/30	1			Q92793-2
CREBBP	ENST00000570939.2 linkuse as main transcript	c.1283C>T	p.Ser428Leu	missense_variant	9/23	5

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

206

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.000720

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:

0.00190

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000987

AC:

248

AN:

251368

Hom.:

AF XY:

0.000949

AC XY:

129

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00187

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00210

AC:

3064

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00198

AC XY:

1442

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000243

Gnomad4 NFE exome

AF:

0.00261

Gnomad4 OTH exome

AF:

0.00192

GnomAD4 genome

AF:

0.00135

AC:

206

AN:

152204

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00190

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00170

Hom.:

Bravo

AF:

0.00182

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.000848

AC:

103

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 11, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2013	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Rubinstein-Taybi syndrome due to CREBBP mutations

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 19, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Rubinstein-Taybi syndrome due to CREBBP mutations;C5193034:Menke-Hennekam syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 04, 2022

- -

CREBBP-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2019

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

Rubinstein-Taybi syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

Cadd

Pathogenic

Dann

Uncertain

0.97

DEOGEN2

Uncertain

0.64

D;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.8

N;N;.

REVEL

Uncertain

0.57

Sift

Benign

0.070

T;T;.

Sift4G

Benign

0.35

T;T;.

Polyphen

0.96

D;.;.

Vest4

0.82

MVP

0.92

MPC

0.079

ClinPred

0.053

GERP RS

5.3

Varity_R

0.11

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.30

Position offset: -14

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over