Variant rs112906840 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_004380.3(CREBBP):c.5933A>T(p.Asn1978Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,802 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1978S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CREBBP
NM_004380.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.38

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREBBP	NM_004380.3 linkuse as main transcript	c.5933A>T	p.Asn1978Ile	missense_variant	31/31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10 linkuse as main transcript	c.5933A>T	p.Asn1978Ile	missense_variant	31/31	1	NM_004380.3	ENSP00000262367	P1	Q92793-1
CREBBP	ENST00000382070.7 linkuse as main transcript	c.5819A>T	p.Asn1940Ile	missense_variant	30/30	1		ENSP00000371502		Q92793-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000494

AC:

AN:

202582

Hom.:

AF XY:

0.00

AC XY:

AN XY:

110892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000368

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1429802

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710260

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000120

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000831

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Uncertain

0.55

D;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.042

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.0

L;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.5

D;D

REVEL

Uncertain

0.34

Sift

Benign

0.18

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.0

B;.

Vest4

0.61

MutPred

0.50

Gain of sheet (P = 0.0061);.;

MVP

0.88

MPC

0.48

ClinPred

0.20

GERP RS

5.0

Varity_R

0.23

gMVP

0.40

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over