rs1555196984
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003482.4(KMT2D):c.2263dupC(p.Arg755fs) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
KMT2D
NM_003482.4 frameshift
NM_003482.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.59
Genes affected
KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]
Genome browser will be placed here
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 12-49051419-C-CG is Pathogenic according to our data. Variant chr12-49051419-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KMT2D | NM_003482.4 | c.2263dupC | p.Arg755fs | frameshift_variant | 11/55 | ENST00000301067.12 | NP_003473.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KMT2D | ENST00000301067.12 | c.2263dupC | p.Arg755fs | frameshift_variant | 11/55 | 5 | NM_003482.4 | ENSP00000301067.7 | ||
KMT2D | ENST00000683543.2 | c.2263dupC | p.Arg755fs | frameshift_variant | 11/56 | ENSP00000506726.1 | ||||
KMT2D | ENST00000685166.1 | c.2263dupC | p.Arg755fs | frameshift_variant | 10/54 | ENSP00000509386.1 | ||||
KMT2D | ENST00000692637.1 | c.2263dupC | p.Arg755fs | frameshift_variant | 10/54 | ENSP00000509666.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 37
GnomAD4 exome
Cov.:
37
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Kabuki syndrome 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Dec 14, 2021 | The KMT2D c.2263dup variant is located in exon 11/55 and is predicted to cause a shift in the reading frame at codon 755, resulting in premature termination and likely non-sense mediated decay of the resulting protein product (PVS1). This variant has been identified as a de novo variant in this patient with no family history of this condition and de novo variants are a known mechanism of disease (PS2). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs1555196984). The variant has been reported as Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 547407). This variant has not been reported in the HGMD disease database. - |
Likely pathogenic, no assertion criteria provided | research | Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University | Sep 30, 2021 | - - |
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