16-3729209-TGG-TG
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_004380.3(CREBBP):c.5837delC(p.Pro1946HisfsTer30) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000146 in 205,426 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_004380.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CREBBP | NM_004380.3 | c.5837delC | p.Pro1946HisfsTer30 | frameshift_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.5837delC | p.Pro1946HisfsTer30 | frameshift_variant | Exon 31 of 31 | 1 | NM_004380.3 | ENSP00000262367.5 | ||
CREBBP | ENST00000382070.7 | c.5723delC | p.Pro1908HisfsTer30 | frameshift_variant | Exon 30 of 30 | 1 | ENSP00000371502.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.0000146 AC: 3AN: 205426Hom.: 0 Cov.: 38 AF XY: 0.00000926 AC XY: 1AN XY: 107994
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
PVS1, PS4_Moderate -
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Rubinstein-Taybi syndrome Pathogenic:1
This sequence change creates a premature translational stop signal (p.Pro1946Hisfs*30) in the CREBBP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 497 amino acid(s) of the CREBBP protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of CREBBP-related conditions and/or Rubinstein-Taybi syndrome (PMID: 25388907, 30586318, 31637876; Invitae). ClinVar contains an entry for this variant (Variation ID: 158391). This variant disrupts a region of the CREBBP protein in which other variant(s) (p.Arg2004*) have been determined to be pathogenic (PMID: 15706485, 21932317). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Rubinstein-Taybi syndrome due to CREBBP mutations Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at