rs1057517753
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_194454.3(KRIT1):c.1201_1204delCAAA(p.Gln401fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
KRIT1
NM_194454.3 frameshift
NM_194454.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.54
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-92225769-TTTTG-T is Pathogenic according to our data. Variant chr7-92225769-TTTTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 372398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92225769-TTTTG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KRIT1 | ENST00000394505.7 | c.1201_1204delCAAA | p.Gln401fs | frameshift_variant | 12/19 | 1 | NM_194454.3 | ENSP00000378013.2 | ||
ENSG00000289027 | ENST00000692281.1 | c.1201_1204delCAAA | p.Gln401fs | frameshift_variant | 12/26 | ENSP00000510568.1 | ||||
ENSG00000285953 | ENST00000458493.6 | c.1201_1204delCAAA | p.Gln401fs | frameshift_variant | 11/20 | 4 | ENSP00000396352.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459096Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726050
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 05, 2024 | PP1_strong, PP4, PM2, PS4_moderate, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 18, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23595507, 27649701, 22699465, 18300272, 20884211, 18383594, 33651268) - |
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 14, 2016 | - - |
Cerebral cavernous malformation Pathogenic:2Uncertain:1
Uncertain significance, flagged submission | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP4,PP5. - |
Pathogenic, no assertion criteria provided | research | Laboratory of Medical Genetics, University of Torino | Oct 06, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 12, 2023 | This sequence change creates a premature translational stop signal (p.Gln401Thrfs*10) in the KRIT1 gene. It is expected to result in an absent or disrupted protein product. 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 premature translational stop signal has been observed in individual(s) with cerebral cavernous malformations (PMID: 2359550, 18300272, 20884211, 22699465, 27649701; Invitae). This variant is also known as c.1197_1200delCAAA. ClinVar contains an entry for this variant (Variation ID: 372398). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cavernous hemangioma of brain Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jun 20, 2022 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at