19-35718132-CG-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_014727.3(KMT2B):c.118del(p.Ala40ProfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G39G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
KMT2B
NM_014727.3 frameshift
NM_014727.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.200
Genes affected
KMT2B (HGNC:15840): (lysine methyltransferase 2B) This gene encodes a protein which contains multiple domains including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains, and a SET (suppressor of variegation, enhancer of zeste, and trithorax) domain. The SET domain is a conserved C-terminal domain that characterizes proteins of the MLL (mixed-lineage leukemia) family. This gene is ubiquitously expressed in adult tissues. It is also amplified in solid tumor cell lines, and may be involved in human cancer. Two alternatively spliced transcript variants encoding distinct isoforms have been reported for this gene, however, the full length nature of the shorter transcript is not known. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 19-35718132-CG-C is Pathogenic according to our data. Variant chr19-35718132-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 870575.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KMT2B | NM_014727.3 | c.118del | p.Ala40ProfsTer6 | frameshift_variant | 1/37 | ENST00000420124.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KMT2B | ENST00000420124.4 | c.118del | p.Ala40ProfsTer6 | frameshift_variant | 1/37 | 1 | NM_014727.3 | P2 | |
KMT2B | ENST00000673918.2 | c.118del | p.Ala40ProfsTer6 | frameshift_variant | 1/37 | A2 | |||
KMT2B | ENST00000692961.1 | c.118del | p.Ala40ProfsTer6 | frameshift_variant, NMD_transcript_variant | 1/36 | ||||
KMT2B | ENST00000687718.1 | c.118del | p.Ala40ProfsTer6 | frameshift_variant, NMD_transcript_variant | 1/3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Dystonia 28, childhood-onset Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Mar 06, 2019 | Observed in proband and identical twin brother. - |
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
Find out detailed SpliceAI scores and Pangolin per-transcript scores at