chr12-49029232-C-G
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2
The NM_003482.4(KMT2D):c.14080G>C(p.Glu4694Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000115 in 1,610,704 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 1 hom. )
Consequence
KMT2D
NM_003482.4 missense
NM_003482.4 missense
Scores
2
6
10
Clinical Significance
Conservation
PhyloP100: 4.97
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, KMT2D
BP4
?
Computational evidence support a benign effect (MetaRNN=0.014107972).
BS2
?
High AC in GnomAd at 13 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KMT2D | NM_003482.4 | c.14080G>C | p.Glu4694Gln | missense_variant | 45/55 | ENST00000301067.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KMT2D | ENST00000301067.12 | c.14080G>C | p.Glu4694Gln | missense_variant | 45/55 | 5 | NM_003482.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152208Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.000586 AC: 146AN: 248970Hom.: 1 AF XY: 0.000481 AC XY: 65AN XY: 135076
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GnomAD4 exome AF: 0.000118 AC: 172AN: 1458496Hom.: 1 Cov.: 32 AF XY: 0.000105 AC XY: 76AN XY: 724782
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GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74364
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:1Other:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 07, 2014 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Kabuki syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Kabuki syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2021 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Benign
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at