chr16-3728362-C-T

Position:

chr16-3728362-C-T

Variant summary

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

The NM_004380.3(CREBBP):c.6685G>A(p.Gly2229Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,607,362 control chromosomes in the GnomAD database, including 17 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 (★★).

Frequency

Genomes: 𝑓 0.0047 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 9 hom. )

Consequence

CREBBP
NM_004380.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -1.09

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 -19 ACMG points.

PP2

Missense variant where missense usually causes diseases, CREBBP

BP4

Computational evidence support a benign effect (MetaRNN=0.004820019).

BP6

Variant 16-3728362-C-T is Benign according to our data. Variant chr16-3728362-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3728362-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00474 (720/152050) while in subpopulation AFR AF= 0.0149 (617/41482). AF 95% confidence interval is 0.0139. There are 8 homozygotes in gnomad4. There are 343 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 720 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3 linkuse as main transcript	c.6685G>A	p.Gly2229Ser	missense_variant	31/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10 linkuse as main transcript	c.6685G>A	p.Gly2229Ser	missense_variant	31/31	1	NM_004380.3	P1	Q92793-1
CREBBP	ENST00000382070.7 linkuse as main transcript	c.6571G>A	p.Gly2191Ser	missense_variant	30/30	1			Q92793-2

Frequencies

GnomAD3 genomes

AF:

0.00474

AC:

720

AN:

151934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000648

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00195

AC:

446

AN:

228750

Hom.:

AF XY:

0.00167

AC XY:

209

AN XY:

125022

show subpopulations

Gnomad AFR exome

AF:

0.0169

Gnomad AMR exome

AF:

0.000703

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000503

Gnomad FIN exome

AF:

0.00322

Gnomad NFE exome

AF:

0.000925

Gnomad OTH exome

AF:

0.00158

GnomAD4 exome

AF:

0.00119

AC:

1725

AN:

1455312

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

832

AN XY:

723684

show subpopulations

Gnomad4 AFR exome

AF:

0.0137

Gnomad4 AMR exome

AF:

0.000599

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000373

Gnomad4 FIN exome

AF:

0.00258

Gnomad4 NFE exome

AF:

0.000880

Gnomad4 OTH exome

AF:

0.00165

GnomAD4 genome

AF:

0.00474

AC:

720

AN:

152050

Hom.:

Cov.:

AF XY:

0.00461

AC XY:

343

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0149

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00330

Gnomad4 NFE

AF:

0.000648

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00144

Hom.:

Bravo

AF:

0.00541

ESP6500AA

AF:

0.0155

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00237

AC:

287

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2024	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 24, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -

Rubinstein-Taybi syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2018

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

0.050

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.29

DANN

Benign

0.67

DEOGEN2

Uncertain

0.43

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.26

N;.

MutationTaster

Benign

0.96

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.17

Sift

Benign

0.49

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.0030

B;.

Vest4

0.064

MVP

0.59

MPC

0.38

ClinPred

0.0014

GERP RS

-6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.20

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