chr16-3728423-T-G

Position:

• chr16-3728423-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000262367.10(CREBBP):​c.6624A>C​(p.Gln2208His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,612,542 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: CREBBP ENST00000262367.10 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• 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

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CREBBP. . Gene score misZ 3.8991 (greater than the threshold 3.09). Trascript score misZ 4.7573 (greater than threshold 3.09). GenCC has associacion of gene with Menke-Hennekam syndrome 1, Rubinstein-Taybi syndrome due to CREBBP mutations, Rubinstein-Taybi syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008503854).
• BP6: Variant 16-3728423-T-G is Benign according to our data. Variant chr16-3728423-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 158398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3728423-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00177 (269/152058) while in subpopulation NFE AF= 0.00172 (117/67924). AF 95% confidence interval is 0.00147. There are 1 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 269 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.6624A>C	p.Gln2208His	missense_variant	31/31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.6624A>C	p.Gln2208His	missense_variant	31/31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.6510A>C	p.Gln2170His	missense_variant	30/30	1		ENSP00000371502.3

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 151940 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00187 AC: 459 AN: 245788 Hom.: 3 AF XY: 0.00176 AC XY: 235 AN XY: 133484

Gnomad AFR exome AF: 0.000441

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00846

Gnomad NFE exome AF: 0.00227

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00163 AC: 2378 AN: 1460484 Hom.: 5 Cov.: 33 AF XY: 0.00157 AC XY: 1138 AN XY: 726536

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00899

Gnomad4 NFE exome AF: 0.00163

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152058 Hom.: 1 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74368

Gnomad4 AFR AF: 0.000386

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0120

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000477 Hom.: 0

Bravo AF: 0.000967

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ExAC AF: 0.00192 AC: 233

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2019	This variant is associated with the following publications: (PMID: 16021471, 25659731) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	CREBBP: BS1 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 04, 2015	- -

Rubinstein-Taybi syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2017

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	3.3
DANN	Benign	0.22
DEOGEN2	Uncertain	0.60	D;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.0085	T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.17	T;T
Polyphen		0.99	D;.
Vest4		0.36
MutPred		0.24		Gain of MoRF binding (P = 0.1375);.;
MVP		0.83
MPC		0.36
ClinPred		0.062	T
GERP RS		-3.5
Varity_R		0.39
gMVP		0.56

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: COSV52122443; COSMIC: COSV52122443;