16-3781229-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_004380.3(CREBBP):c.1651C>A(p.Leu551Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00973 in 1,613,964 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0076 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0099 ( 140 hom. )

Consequence

CREBBP
NM_004380.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8O:1

Conservation

PhyloP100: 5.82

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 -12 ACMG points.

PP2

Missense variant in the CREBBP gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 165 curated benign missense variants. Gene score misZ: 3.8991 (above the threshold of 3.09). Trascript score misZ: 4.7573 (above the threshold of 3.09). GenCC associations: The gene is linked to Menke-Hennekam syndrome 1, Rubinstein-Taybi syndrome due to CREBBP mutations, Rubinstein-Taybi syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.007070422).

BP6

Variant 16-3781229-G-T is Benign according to our data. Variant chr16-3781229-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95026.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1, not_provided=1}. Variant chr16-3781229-G-T is described in Lovd as [Benign]. Variant chr16-3781229-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00764 (1163/152270) while in subpopulation EAS AF= 0.0129 (67/5186). AF 95% confidence interval is 0.0104. There are 13 homozygotes in gnomad4. There are 565 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1163 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3 link	c.1651C>A	p.Leu551Ile	missense_variant	Exon 7 of 31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CREBBP	ENST00000262367.10 link	c.1651C>A	p.Leu551Ile	missense_variant	Exon 7 of 31	1	NM_004380.3	ENSP00000262367.5	Q92793-1
CREBBP	ENST00000382070.7 link	c.1537C>A	p.Leu513Ile	missense_variant	Exon 6 of 30	1		ENSP00000371502.3	Q92793-2
CREBBP	ENST00000570939.2 link	c.256C>A	p.Leu86Ile	missense_variant	Exon 2 of 23	5		ENSP00000461002.2	I3L466

Frequencies

GnomAD3 genomes

AF:

0.00765

AC:

1164

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00858

Gnomad ASJ

AF:

0.0617

Gnomad EAS

AF:

0.0131

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00844

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.0103

AC:

2584

AN:

251442

Hom.:

AF XY:

0.0109

AC XY:

1481

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00509

Gnomad ASJ exome

AF:

0.0592

Gnomad EAS exome

AF:

0.0164

Gnomad SAS exome

AF:

0.0112

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.00908

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.00995

AC:

14541

AN:

1461694

Hom.:

140

Cov.:

AF XY:

0.0102

AC XY:

7437

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00185

Gnomad4 AMR exome

AF:

0.00555

Gnomad4 ASJ exome

AF:

0.0583

Gnomad4 EAS exome

AF:

0.0236

Gnomad4 SAS exome

AF:

0.0113

Gnomad4 FIN exome

AF:

0.00187

Gnomad4 NFE exome

AF:

0.00868

Gnomad4 OTH exome

AF:

0.0137

GnomAD4 genome

AF:

0.00764

AC:

1163

AN:

152270

Hom.:

Cov.:

AF XY:

0.00759

AC XY:

565

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00173

Gnomad4 AMR

AF:

0.00857

Gnomad4 ASJ

AF:

0.0617

Gnomad4 EAS

AF:

0.0129

Gnomad4 SAS

AF:

0.0114

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.00844

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0119

Hom.:

Bravo

AF:

0.00774

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00205

AC:

ESP6500EA

AF:

0.0121

AC:

104

ExAC

AF:

0.0100

AC:

1214

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0136

EpiControl

AF:

0.0121

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:4Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 18, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 31, 2014

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Nov 04, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Rubinstein-Taybi syndrome

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 27, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.087

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Uncertain

0.47

T;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.79

T;T;T

MetaRNN

Benign

0.0071

T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.2

L;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.1

N;N;.

REVEL

Uncertain

0.38

Sift

Benign

0.052

T;D;.

Sift4G

Benign

0.30

T;T;.

Polyphen

0.60

P;.;.

Vest4

0.23

MPC

1.3

ClinPred

0.017

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.19

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