rs129967

Variant names:

• chr16-3739536-G-A
• rs129967
• NM_004380.3:c.4280+42C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-3739536-G-A
• chr16-3739536-G-C
• chr16-3739536-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004380.3(CREBBP):​c.4280+42C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,612,982 control chromosomes in the GnomAD database, including 9,585 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (4131 hom., cov: 33)
  • Exomes 𝑓: 0.038 (5454 hom.)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.192
• Publications: 6 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 (BayesDel_noAF=-0.97).
• BP6: Variant 16-3739536-G-A is Benign according to our data. Variant chr16-3739536-G-A is described in ClinVar as [Benign]. Clinvar id is 1242603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.4280+42C>T		intron_variant	Intron 25 of 30	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.4280+42C>T		intron_variant	Intron 25 of 30	1	NM_004380.3	ENSP00000262367.5

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22038 AN: 152006 Hom.: 4113 Cov.: 33

Gnomad AFR AF: 0.428

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0728

Gnomad ASJ AF: 0.0850

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.126

GnomAD2 exomes AF: 0.0759 AC: 19019 AN: 250528 AF XY: 0.0711

Gnomad AFR exome AF: 0.448

Gnomad AMR exome AF: 0.0369

Gnomad ASJ exome AF: 0.0752

Gnomad EAS exome AF: 0.220

Gnomad FIN exome AF: 0.00301

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0513

GnomAD4 exome AF: 0.0376 AC: 54889 AN: 1460858 Hom.: 5454 Cov.: 31 AF XY: 0.0388 AC XY: 28225 AN XY: 726724

African (AFR) AF: 0.450 AC: 15046 AN: 33432

American (AMR) AF: 0.0417 AC: 1862 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0780 AC: 2038 AN: 26124

East Asian (EAS) AF: 0.193 AC: 7640 AN: 39662

South Asian (SAS) AF: 0.121 AC: 10411 AN: 86172

European-Finnish (FIN) AF: 0.00414 AC: 221 AN: 53396

Middle Eastern (MID) AF: 0.0789 AC: 446 AN: 5654

European-Non Finnish (NFE) AF: 0.0118 AC: 13090 AN: 1111406

Other (OTH) AF: 0.0685 AC: 4135 AN: 60352

GnomAD4 genome AF: 0.145 AC: 22100 AN: 152124 Hom.: 4131 Cov.: 33 AF XY: 0.142 AC XY: 10584 AN XY: 74378

African (AFR) AF: 0.428 AC: 17743 AN: 41438

American (AMR) AF: 0.0727 AC: 1111 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0850 AC: 295 AN: 3472

East Asian (EAS) AF: 0.205 AC: 1062 AN: 5180

South Asian (SAS) AF: 0.130 AC: 628 AN: 4814

European-Finnish (FIN) AF: 0.00340 AC: 36 AN: 10598

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0129 AC: 875 AN: 68024

Other (OTH) AF: 0.125 AC: 264 AN: 2110

Alfa AF: 0.0640 Hom.: 1929

Bravo AF: 0.165

Asia WGS AF: 0.183 AC: 638 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.3
DANN	Benign	0.60
PhyloP100		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs129967; hg19: chr16-3789537; COSMIC: COSV52117696; COSMIC: COSV52117696;