16-3729247-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004380.3(CREBBP):c.5800T>C(p.Ser1934Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000375 in 1,526,834 control chromosomes in the GnomAD database, including 1 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 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 1 hom. )

Consequence

CREBBP
NM_004380.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:5

Conservation

PhyloP100: 5.09

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

Rubinstein-Taybi syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
Rubinstein-Taybi syndrome due to CREBBP mutations
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
Menke-Hennekam syndrome 1
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CREBBP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056996673).

BP6

Variant 16-3729247-A-G is Benign according to our data. Variant chr16-3729247-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158387. Variant chr16-3729247-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158387. Variant chr16-3729247-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158387. Variant chr16-3729247-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 158387.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000293 (44/150386) while in subpopulation NFE AF = 0.000548 (37/67498). AF 95% confidence interval is 0.000408. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3 link	c.5800T>C	p.Ser1934Pro	missense_variant	Exon 31 of 31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10 link	c.5800T>C	p.Ser1934Pro	missense_variant	Exon 31 of 31	1	NM_004380.3	ENSP00000262367.5		Q92793-1
CREBBP	ENST00000382070.7 link	c.5686T>C	p.Ser1896Pro	missense_variant	Exon 30 of 30	1		ENSP00000371502.3		Q92793-2

Frequencies

GnomAD3 genomes

AF:

0.000299

AC:

AN:

150270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000492

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.000867

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000548

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.000350

AC:

AN:

131462

AF XY:

0.000323

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000410

Gnomad ASJ exome

AF:

0.00103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000715

Gnomad OTH exome

AF:

0.000249

GnomAD4 exome

AF:

0.000384

AC:

528

AN:

1376448

Hom.:

Cov.:

AF XY:

0.000373

AC XY:

253

AN XY:

678226

show subpopulations

African (AFR)

AF:

0.0000637

AC:

AN:

31406

American (AMR)

AF:

0.000169

AC:

AN:

35522

Ashkenazi Jewish (ASJ)

AF:

0.00141

AC:

AN:

24798

East Asian (EAS)

AF:

0.00

AC:

AN:

35618

South Asian (SAS)

AF:

0.000102

AC:

AN:

78612

European-Finnish (FIN)

AF:

0.0000583

AC:

AN:

34292

Middle Eastern (MID)

AF:

0.00145

AC:

AN:

4152

European-Non Finnish (NFE)

AF:

0.000418

AC:

449

AN:

1074618

Other (OTH)

AF:

0.000348

AC:

AN:

57430

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000293

AC:

AN:

150386

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

AN XY:

73396

show subpopulations

African (AFR)

AF:

0.0000491

AC:

AN:

40758

American (AMR)

AF:

0.0000659

AC:

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.000867

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5056

South Asian (SAS)

AF:

0.00

AC:

AN:

4762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000548

AC:

AN:

67498

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000941

Hom.:

Bravo

AF:

0.000423

ExAC

AF:

0.0000709

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Mar 23, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CREBBP: PP2, BS1, BS2 -

Apr 01, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tip-toe gait

Pathogenic:1

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

Rubinstein-Taybi syndrome due to CREBBP mutations

Uncertain:1

Jan 23, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CREBBP-related disorder

Benign:1

Jul 16, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jun 09, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.53

D;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.041

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.057

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.95

L;.

PhyloP100

5.1

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.48

Sift

Benign

0.068

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.014

B;.

Vest4

0.10

MVP

0.99

MPC

1.6

ClinPred

0.056

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.20

Mutation Taster

=69/31

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over