chr16-3729247-A-G

Position:

• chr16-3729247-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_004380.3(CREBBP):​c.5800T>C​(p.Ser1934Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000375 in 1,526,834 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:5
• Conservation: PhyloP100: 5.09

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 -12 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=0.056996673).
• BP6: Variant 16-3729247-A-G is Benign according to our data. Variant chr16-3729247-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158387.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000293 (44/150386) while in subpopulation NFE AF= 0.000548 (37/67498). AF 95% confidence interval is 0.000408. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.5800T>C	p.Ser1934Pro	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.5800T>C	p.Ser1934Pro	missense_variant	31/31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.5686T>C	p.Ser1896Pro	missense_variant	30/30	1		ENSP00000371502.3

Frequencies

GnomAD3 genomes AF: 0.000299 AC: 45 AN: 150270 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.000867

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000548

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.000350 AC: 46 AN: 131462 Hom.: 0 AF XY: 0.000323 AC XY: 23 AN XY: 71186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000410

Gnomad ASJ exome AF: 0.00103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000715

Gnomad OTH exome AF: 0.000249

GnomAD4 exome AF: 0.000384 AC: 528 AN: 1376448 Hom.: 1 Cov.: 35 AF XY: 0.000373 AC XY: 253 AN XY: 678226

Gnomad4 AFR exome AF: 0.0000637

Gnomad4 AMR exome AF: 0.000169

Gnomad4 ASJ exome AF: 0.00141

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000102

Gnomad4 FIN exome AF: 0.0000583

Gnomad4 NFE exome AF: 0.000418

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000293 AC: 44 AN: 150386 Hom.: 0 Cov.: 32 AF XY: 0.000300 AC XY: 22 AN XY: 73396

Gnomad4 AFR AF: 0.0000491

Gnomad4 AMR AF: 0.0000659

Gnomad4 ASJ AF: 0.000867

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000548

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000941 Hom.: 0

Bravo AF: 0.000423

ExAC AF: 0.0000709 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CREBBP: PP2, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2020	- -

Tip-toe gait Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

-

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

Rubinstein-Taybi syndrome due to CREBBP mutations Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 23, 2014

- -

CREBBP-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Rubinstein-Taybi syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

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	0.087
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Uncertain	0.53	D;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.95	L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.48
Sift	Benign	0.068	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.014	B;.
Vest4		0.10
MVP		0.99
MPC		1.6
ClinPred		0.056	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.20

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: rs587783504; hg19: chr16-3779248; COSMIC: COSV105864154; COSMIC: COSV105864154;