rs149961222

Positions:

chr16-3810683-T-C

Variant summary

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

The NM_004380.3(CREBBP):c.895A>G(p.Ser299Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

CREBBP
NM_004380.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 2.34

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=0.008075535).

BP6

Variant 16-3810683-T-C is Benign according to our data. Variant chr16-3810683-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 133934.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 = 0.000755 (115/152228) while in subpopulation AFR AF= 0.00262 (109/41552). AF 95% confidence interval is 0.00222. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 115 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREBBP	NM_004380.3 linkuse as main transcript	c.895A>G	p.Ser299Gly	missense_variant	3/31	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.895A>G	p.Ser299Gly	missense_variant	3/31	1	NM_004380.3	ENSP00000262367.5	Q92793-1
CREBBP	ENST00000382070.7 linkuse as main transcript	c.895A>G	p.Ser299Gly	missense_variant	3/30	1		ENSP00000371502.3	Q92793-2
CREBBP	ENST00000635899.1 linkuse as main transcript	n.*37A>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000763

AC:

116

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000147

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251454

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.0000289

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000609

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00239

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000755

AC:

115

AN:

152228

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00262

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000118

Hom.:

Bravo

AF:

0.000722

ESP6500AA

AF:

0.00228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000239

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CREBBP-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2021

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). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Uncertain

0.43

T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.0081

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.17

Sift

Benign

0.040

D;D

Sift4G

Benign

0.31

T;T

Polyphen

0.73

P;.

Vest4

0.077

MVP

0.82

MPC

0.14

ClinPred

0.017

GERP RS

4.2

Varity_R

0.066

gMVP

0.17

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