chr16-3729445-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_004380.3(CREBBP):c.5602C>T(p.Arg1868Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1868Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CREBBP
NM_004380.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.42

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 Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-3729444-C-T is described in Lovd as [Likely_pathogenic].

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

PP5

Variant 16-3729445-G-A is Pathogenic according to our data. Variant chr16-3729445-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 265346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3729445-G-A is described in Lovd as [Likely_pathogenic]. Variant chr16-3729445-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3 link	c.5602C>T	p.Arg1868Trp	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.5602C>T	p.Arg1868Trp	missense_variant	Exon 31 of 31	1	NM_004380.3	ENSP00000262367.5		Q92793-1
CREBBP	ENST00000382070.7 link	c.5488C>T	p.Arg1830Trp	missense_variant	Exon 30 of 30	1		ENSP00000371502.3		Q92793-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Menke-Hennekam syndrome 1

Pathogenic:4

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.67; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000265346 / PMID: 27311832) and a different missense change at the same codon (p.Arg1868Gln / ClinVar ID: VCV000598959 / PMID: 29460469) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 22, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 15, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Oct 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29460469, 30892814, 27311832, 29159939, 33057194, 35904121, 36939041, 35982159, 37353886, 37010288) -

See cases

Pathogenic:1

Dec 21, 2022

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Menke-Hennekam syndrome

Pathogenic:1

Jul 15, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CREBBP c.5602C>T (p.Arg1868Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250920 control chromosomes. c.5602C>T has been reported in the literature as a de-novo variant in multiple individuals with CREBBP-related disorders lacking the characteristic facial and limb dysmorphism associated with RubinsteinTaybi syndrome (RTS), specifically called as Menke-Hennekam syndrome (example, Menke_2018, Banka_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.97

D;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-7.8

D;D

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.96

MutPred

0.39

Gain of helix (P = 0.0225);.;

MVP

0.97

MPC

1.4

ClinPred

1.0

GERP RS

3.5

Varity_R

0.89

gMVP

0.88

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