16-3729161-G-T

Variant names:

• chr16-3729161-G-T
• rs370565083
• NM_004380.3:c.5886C>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004380.3(CREBBP):​c.5886C>A​(p.Ile1962Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,325,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I1962I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CREBBP NM_004380.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.84
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-3729161-G-T is Benign according to our data. Variant chr16-3729161-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 434829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.84 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 20 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.5886C>A	p.Ile1962Ile	synonymous	Exon 31 of 31	NP_004371.2
	CREBBP	NM_001079846.1		c.5772C>A	p.Ile1924Ile	synonymous	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.5886C>A	p.Ile1962Ile	synonymous	Exon 31 of 31	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.5772C>A	p.Ile1924Ile	synonymous	Exon 30 of 30	ENSP00000371502.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000151 AC: 20 AN: 1325582 Hom.: 0 Cov.: 36 AF XY: 0.0000137 AC XY: 9 AN XY: 655606

African (AFR) AF: 0.00 AC: 0 AN: 29500

American (AMR) AF: 0.00 AC: 0 AN: 34538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22524

East Asian (EAS) AF: 0.00 AC: 0 AN: 29344

South Asian (SAS) AF: 0.00 AC: 0 AN: 79374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4932

European-Non Finnish (NFE) AF: 0.0000192 AC: 20 AN: 1042284

Other (OTH) AF: 0.00 AC: 0 AN: 53686

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Sep 02, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Rubinstein-Taybi syndrome Benign:1

Aug 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.017
DANN	Benign	0.53
PhyloP100		-1.8

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: rs370565083; hg19: chr16-3779162;