chr16-3728423-T-C

Variant names:

• chr16-3728423-T-C
• rs142545779
• NM_004380.3:c.6624A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004380.3(CREBBP):​c.6624A>G​(p.Gln2208Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,612,536 control chromosomes in the GnomAD database, including 47 homozygotes. 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. Q2208QQQQQ) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0092 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: CREBBP NM_004380.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.274

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]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-3728423-T-C is Benign according to our data. Variant chr16-3728423-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 95064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.274 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00916 (1393/152052) while in subpopulation AFR AF = 0.0313 (1298/41468). AF 95% confidence interval is 0.0299. There are 28 homozygotes in GnomAd4. There are 621 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1393 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.6624A>G	p.Gln2208Gln	synonymous_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	c.6624A>G	p.Gln2208Gln	synonymous_variant	Exon 31 of 31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.6510A>G	p.Gln2170Gln	synonymous_variant	Exon 30 of 30	1		ENSP00000371502.3

Frequencies

GnomAD3 genomes AF: 0.00915 AC: 1390 AN: 151934 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.00248 AC: 609 AN: 245788 AF XY: 0.00180

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.000995

GnomAD4 exome AF: 0.00113 AC: 1644 AN: 1460484 Hom.: 19 Cov.: 33 AF XY: 0.00100 AC XY: 729 AN XY: 726536

Gnomad4 AFR exome AF: 0.0309 AC: 1032 AN: 33450

Gnomad4 AMR exome AF: 0.00123 AC: 55 AN: 44686

Gnomad4 ASJ exome AF: 0.000153 AC: 4 AN: 26114

Gnomad4 EAS exome AF: 0.00131 AC: 52 AN: 39672

Gnomad4 SAS exome AF: 0.000128 AC: 11 AN: 86134

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53252

Gnomad4 NFE exome AF: 0.000323 AC: 359 AN: 1111122

Gnomad4 Remaining exome AF: 0.00209 AC: 126 AN: 60292

GnomAD4 genome AF: 0.00916 AC: 1393 AN: 152052 Hom.: 28 Cov.: 32 AF XY: 0.00835 AC XY: 621 AN XY: 74364

Gnomad4 AFR AF: 0.0313 AC: 0.0313012 AN: 0.0313012

Gnomad4 AMR AF: 0.00255 AC: 0.00255069 AN: 0.00255069

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00232 AC: 0.00232288 AN: 0.00232288

Gnomad4 SAS AF: 0.000208 AC: 0.00020842 AN: 0.00020842

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000412 AC: 0.000412225 AN: 0.000412225

Gnomad4 OTH AF: 0.00712 AC: 0.00711575 AN: 0.00711575

Alfa AF: 0.000557 Hom.: 0

Bravo AF: 0.0107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 18, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 07, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rubinstein-Taybi syndrome due to CREBBP mutations;C5193034:Menke-Hennekam syndrome 1 Benign:1

Jan 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jul 28, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Rubinstein-Taybi syndrome Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.83
CADD	Benign	0.068
DANN	Benign	0.22
Mutation Taster		=95/5	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

Publications

LitVar

Other links and lift over

dbSNP: rs142545779; hg19: chr16-3778424; COSMIC: COSV99269710; COSMIC: COSV99269710;