NM_004380.3:c.5933A>G

Variant names:

• chr16-3729114-T-C
• rs112906840
• NM_004380.3:c.5933A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004380.3(CREBBP):​c.5933A>G​(p.Asn1978Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00542 in 1,581,462 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1978K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (24 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 3.38
• Publications: 24 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054739416).
• BP6: Variant 16-3729114-T-C is Benign according to our data. Variant chr16-3729114-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00427 (647/151668) while in subpopulation NFE AF = 0.00627 (425/67818). AF 95% confidence interval is 0.00577. There are 3 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 647 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004380.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	NM_004380.3	MANE Select	c.5933A>G	p.Asn1978Ser	missense	Exon 31 of 31	NP_004371.2
	CREBBP	NM_001079846.1		c.5819A>G	p.Asn1940Ser	missense	Exon 30 of 30	NP_001073315.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	ENST00000262367.10	TSL:1 MANE Select	c.5933A>G	p.Asn1978Ser	missense	Exon 31 of 31	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.5819A>G	p.Asn1940Ser	missense	Exon 30 of 30	ENSP00000371502.3

Frequencies

GnomAD3 genomes AF: 0.00427 AC: 647 AN: 151544 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00703

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00627

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00505 AC: 1024 AN: 202582 AF XY: 0.00492

Gnomad AFR exome AF: 0.000873

Gnomad AMR exome AF: 0.00364

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00914

Gnomad NFE exome AF: 0.00689

Gnomad OTH exome AF: 0.00662

GnomAD4 exome AF: 0.00554 AC: 7925 AN: 1429794 Hom.: 24 Cov.: 34 AF XY: 0.00545 AC XY: 3870 AN XY: 710252

African (AFR) AF: 0.000729 AC: 24 AN: 32936

American (AMR) AF: 0.00319 AC: 134 AN: 42014

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 391 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 38286

South Asian (SAS) AF: 0.000192 AC: 16 AN: 83426

European-Finnish (FIN) AF: 0.00839 AC: 337 AN: 40190

Middle Eastern (MID) AF: 0.00244 AC: 14 AN: 5732

European-Non Finnish (NFE) AF: 0.00604 AC: 6653 AN: 1102050

Other (OTH) AF: 0.00599 AC: 356 AN: 59408

GnomAD4 genome AF: 0.00427 AC: 647 AN: 151668 Hom.: 3 Cov.: 32 AF XY: 0.00403 AC XY: 299 AN XY: 74136

African (AFR) AF: 0.00121 AC: 50 AN: 41398

American (AMR) AF: 0.00288 AC: 44 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4788

European-Finnish (FIN) AF: 0.00703 AC: 74 AN: 10530

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00627 AC: 425 AN: 67818

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00539 Hom.: 2

Bravo AF: 0.00420

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00594 AC: 51

ExAC AF: 0.00469 AC: 564

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (5)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Rubinstein-Taybi syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.0095
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.26
Sift	Benign	0.34	T
Sift4G	Benign	0.79	T
Polyphen		0.12	B
Vest4		0.14
MVP		0.77
MPC		0.30
ClinPred		0.0060	T
GERP RS		5.0
Varity_R		0.063
gMVP		0.17
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs112906840; hg19: chr16-3779115; COSMIC: COSV52116951; COSMIC: COSV52116951;