rs587783466

Positions:

• chr16-3850931-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_004380.3(CREBBP):​c.164A>G​(p.Asn55Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000424 in 1,461,884 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N55K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000042 (1 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.968

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 -10 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CREBBP
• BP4: Computational evidence support a benign effect (MetaRNN=0.068220496).
• BP6: Variant 16-3850931-T-C is Benign according to our data. Variant chr16-3850931-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158340.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000424 (62/1461884) while in subpopulation SAS AF= 0.000707 (61/86258). AF 95% confidence interval is 0.000564. There are 1 homozygotes in gnomad4_exome. There are 47 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.164A>G	p.Asn55Ser	missense_variant	2/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.164A>G	p.Asn55Ser	missense_variant	2/31	1	NM_004380.3	P1
CREBBP	ENST00000382070.7	c.164A>G	p.Asn55Ser	missense_variant	2/30	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000835 AC: 21 AN: 251354 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461884 Hom.: 1 Cov.: 32 AF XY: 0.0000646 AC XY: 47 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000707

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 03, 2021

- -

Rubinstein-Taybi syndrome due to CREBBP mutations Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 19, 2013

- -

Rubinstein-Taybi syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Benign	0.80
DEOGEN2	Uncertain	0.49	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.42	N;N
MutationTaster	Benign	0.95	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.23
Sift	Benign	0.085	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.14	B;.
Vest4		0.23
MutPred		0.12		Gain of phosphorylation at N55 (P = 0.0792);Gain of phosphorylation at N55 (P = 0.0792);
MVP		0.74
MPC		0.12
ClinPred		0.059	T
GERP RS		2.3
Varity_R		0.065
gMVP		0.16

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: rs587783466; hg19: chr16-3900932;