rs1554514380
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong
The NM_194454.3(KRIT1):c.1255-1_1256del variant causes a splice acceptor, coding sequence change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,596 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
KRIT1
NM_194454.3 splice_acceptor, coding_sequence
NM_194454.3 splice_acceptor, coding_sequence
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.03
Genes affected
KRIT1 (HGNC:1573): (KRIT1 ankyrin repeat containing) This gene encodes a protein containing four ankyrin repeats, a band 4.1/ezrin/radixin/moesin (FERM) domain, and multiple NPXY sequences. The encoded protein is localized in the nucleus and cytoplasm. It binds to integrin cytoplasmic domain-associated protein-1 alpha (ICAP1alpha), and plays a critical role in beta1-integrin-mediated cell proliferation. It associates with junction proteins and RAS-related protein 1A (Rap1A), which requires the encoded protein for maintaining the integrity of endothelial junctions. It is also a microtubule-associated protein and may play a role in microtubule targeting. Mutations in this gene result in cerebral cavernous malformations. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4, offset of -26, new splice context is: gtgatgtataattttttaAGttc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 7-92222976-ATAC-A is Pathogenic according to our data. Variant chr7-92222976-ATAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 468206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92222976-ATAC-A is described in Lovd as [Pathogenic]. Variant chr7-92222976-ATAC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRIT1 | NM_194454.3 | c.1255-1_1256del | splice_acceptor_variant, coding_sequence_variant | 13/19 | ENST00000394505.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRIT1 | ENST00000394505.7 | c.1255-1_1256del | splice_acceptor_variant, coding_sequence_variant | 13/19 | 1 | NM_194454.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.90e-7 AC: 1AN: 1449596Hom.: 0 AF XY: 0.00000139 AC XY: 1AN XY: 722022
GnomAD4 exome
AF:
AC:
1
AN:
1449596
Hom.:
AF XY:
AC XY:
1
AN XY:
722022
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cerebral cavernous malformation Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Aug 17, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 13, 2022 | This variant results in the deletion of part of exon 14 (c.1255-1_1256del) of the KRIT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in KRIT1 are known to be pathogenic (PMID: 10508515, 11222804, 12404106, 24689081). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with cerebral cavernous malformations (PMID: 11914398, 18300272, 24689081). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS13-2delATG. ClinVar contains an entry for this variant (Variation ID: 468206). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
KRIT1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 27, 2023 | The KRIT1 c.1255-1_1256delGTA variant is predicted to result in a deletion affecting a canonical splice site. This variant is predicted to result in an intronic in-frame deletion. This deletion of three nucleotides abolishes the consensus splice acceptor signal and is predicted to result in aberrant splicing (SpliceAI, Jaganathan K, et al. 2019. PubMed ID: 30661751). This variant has been reported multiple times to be causative for cerebral cavernous malformations (CCMs) (Verlaan et al. 2002. PubMed ID: 11914398; Stahl et al. 2008. PubMed ID: 18300272). We have also observed this deletion in several other affected patients at PreventionGenetics. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -8
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at