12-49051149-CG-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PVS1PP5_ModerateBS2
The NM_003482.4(KMT2D):c.2533del(p.Arg845GlyfsTer85) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,359,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R845R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_003482.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KMT2D | NM_003482.4 | c.2533del | p.Arg845GlyfsTer85 | frameshift_variant | 11/55 | ENST00000301067.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KMT2D | ENST00000301067.12 | c.2533del | p.Arg845GlyfsTer85 | frameshift_variant | 11/55 | 5 | NM_003482.4 | A2 | |
KMT2D | ENST00000683543.2 | c.2533del | p.Arg845GlyfsTer85 | frameshift_variant | 11/56 | P4 | |||
KMT2D | ENST00000685166.1 | c.2533del | p.Arg845GlyfsTer85 | frameshift_variant | 10/54 | A2 | |||
KMT2D | ENST00000692637.1 | c.2533del | p.Arg845GlyfsTer85 | frameshift_variant | 10/54 | A2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.0000118 AC: 16AN: 1359590Hom.: 0 Cov.: 33 AF XY: 0.0000180 AC XY: 12AN XY: 667472
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Kabuki syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2017 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in KMT2D are known to be pathogenic (PMID: 22126750). This variant has not been reported in the literature in individuals with KMT2D-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg845Glyfs*85) in the KMT2D gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at