chr17-46171334-CAG-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 9P and 5B. PVS1PP5BS1_SupportingBS2
The NM_015443.4(KANSL1):c.808_809delCT(p.Leu270ValfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_015443.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KANSL1 | NM_015443.4 | c.808_809delCT | p.Leu270ValfsTer11 | frameshift_variant | Exon 2 of 15 | ENST00000432791.7 | NP_056258.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251458Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135898
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461878Hom.: 0 AF XY: 0.0000206 AC XY: 15AN XY: 727244
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 35 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Koolen-de Vries syndrome Pathogenic:3Uncertain:2
Uncertain significance, flagged submission | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 31, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 28, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 18, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 26, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Breda Genetics srl | Jun 23, 2022 | The variant c.808_809del (p.Leu270Valfs*11) in the KANSL1 gene is reported with conflicting interpretations (pathogenic, likely pathogenic, uncertain) in ClinVar for Koolen-de Vries syndrome (Variation ID: 168412) and as likely pathogenic in the LOVD database v.3.0 (genomic variant: #0000795640). The variant c.808_809del (p.Leu270Valfs*11) has been reported as pathogenic by Niar et al. (2018, PMID: 30293248) in a patient with a diagnosis of Koolen-deVries syndrome, which had developmental delay, intellectual disability, hypotony, ptosis, short stature, and ligamentous laxity. The variant creates a shift in the reading frame which is predicted to result in a premature stop codon 11 amino acids downstream, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allele frequency of 0.00002386 in gnomAD exomes and di 0.00003185 in gnomAD genomes with no homozygous individuals reported. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 28, 2023 | The c.808_809delCT (p.L270Vfs*11) alteration, located in exon 2 (coding exon 1) of the KANSL1 gene, consists of a deletion of 2 nucleotides from position 808 to 809, causing a translational frameshift with a predicted alternate stop codon after 11 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.808_809delCT allele has an overall frequency of 0.002% (7/282852) total alleles studied. The highest observed frequency was 0.01% (3/30616) of South Asian alleles. Loss of function alterations in this region of the KANSL1 gene are more common in population databases than expected for likely pathogenic/disease-causing variants (Koolen, 2015). Based on the available evidence, this alteration is classified as pathogenic. - |
KANSL1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 25, 2023 | The KANSL1 c.808_809delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu270Valfs*11). This variant was reported in multiple individuals with Koolen-de Vries syndrome or a neurodevelopmental phenotype. In many cases, the variant arose de novo (Nair et al. 2018. PubMed ID: 30293248; Table S1 - Gabriel et al. 2021. PubMed ID: 34958143; Tolusso et al. 2021. PubMed ID: 33442022; Table S2 - Turner et al. 2019. PubMed ID: 31785789). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-44248700-CAG-C). Frameshift variants in KANSL1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2019 | - - |
not specified Uncertain:1
Uncertain significance, flagged submission | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at