rs61731376

Positions:

Variant summary

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

The NM_004380.3(CREBBP):c.3128C>T(p.Ser1043Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,614,122 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 23 hom., cov: 32)

Exomes 𝑓: 0.00099 ( 16 hom. )

Consequence

CREBBP
NM_004380.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 1.07

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:

CREBBP (HGNC:):

CREBBP links:

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=0.00389117).

BP6

Variant 16-3767842-G-A is Benign according to our data. Variant chr16-3767842-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95042.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 = 0.00996 (1516/152240) while in subpopulation AFR AF= 0.0338 (1404/41544). AF 95% confidence interval is 0.0323. There are 23 homozygotes in gnomad4. There are 698 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1516 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREBBP	NM_004380.3 linkuse as main transcript	c.3128C>T	p.Ser1043Leu	missense_variant	16/31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CREBBP	ENST00000262367.10 linkuse as main transcript	c.3128C>T	p.Ser1043Leu	missense_variant	16/31	1	NM_004380.3	ENSP00000262367.5	Q92793-1
CREBBP	ENST00000382070.7 linkuse as main transcript	c.3014C>T	p.Ser1005Leu	missense_variant	15/30	1		ENSP00000371502.3	Q92793-2
CREBBP	ENST00000570939.2 linkuse as main transcript	c.1733C>T	p.Ser578Leu	missense_variant	11/23	5		ENSP00000461002.2	I3L466
CREBBP	ENST00000573672.1 linkuse as main transcript	n.382C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.00997

AC:

1517

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0339

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00590

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:

0.0000294

Gnomad OTH

AF:

0.00955

GnomAD3 exomes

AF:

0.00267

AC:

671

AN:

251464

Hom.:

AF XY:

0.00199

AC XY:

271

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0355

Gnomad AMR exome

AF:

0.00220

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:

0.0000615

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.000993

AC:

1451

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000825

AC XY:

600

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0340

Gnomad4 AMR exome

AF:

0.00295

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.00214

GnomAD4 genome

AF:

0.00996

AC:

1516

AN:

152240

Hom.:

Cov.:

AF XY:

0.00938

AC XY:

698

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0338

Gnomad4 AMR

AF:

0.00589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00945

Alfa

AF:

0.00161

Hom.:

Bravo

AF:

0.0121

ESP6500AA

AF:

0.0335

AC:

147

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00312

AC:

379

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2013	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

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

Apr 21, 2022

- -

Rubinstein-Taybi syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2016

This 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.54

D;.;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.4

L;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.8

N;N;.

REVEL

Benign

0.19

Sift

Benign

0.30

T;T;.

Sift4G

Benign

0.35

T;T;.

Polyphen

0.010

B;.;.

Vest4

0.17

MVP

0.70

MPC

0.049

ClinPred

0.020

GERP RS

4.6

Varity_R

0.085

gMVP

0.094

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.

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