rs148836047
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_194454.3(KRIT1):c.1752C>T(p.Ile584Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,607,498 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 1 hom. )
Consequence
KRIT1
NM_194454.3 synonymous
NM_194454.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0150
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 Benign. Variant got -19 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.35).
BP6
Variant 7-92213958-G-A is Benign according to our data. Variant chr7-92213958-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92213958-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.015 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000112 (17/152210) while in subpopulation SAS AF= 0.000207 (1/4824). AF 95% confidence interval is 0.000124. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 17 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KRIT1 | NM_194454.3 | c.1752C>T | p.Ile584Ile | synonymous_variant | 16/19 | ENST00000394505.7 | NP_919436.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KRIT1 | ENST00000394505.7 | c.1752C>T | p.Ile584Ile | synonymous_variant | 16/19 | 1 | NM_194454.3 | ENSP00000378013.2 | ||
ENSG00000289027 | ENST00000692281.1 | c.1752C>T | p.Ile584Ile | synonymous_variant | 16/26 | ENSP00000510568.1 | ||||
ENSG00000285953 | ENST00000458493.6 | c.1752C>T | p.Ile584Ile | synonymous_variant | 15/20 | 4 | ENSP00000396352.2 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152092Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000163 AC: 41AN: 251296Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135814
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GnomAD4 exome AF: 0.000203 AC: 295AN: 1455288Hom.: 1 Cov.: 28 AF XY: 0.000204 AC XY: 148AN XY: 724396
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GnomAD4 genome AF: 0.000112 AC: 17AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74414
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ClinVar
Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 06, 2023 | 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. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Cerebral cavernous malformation Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 02, 2021 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at