12-49051742-TGG-TG
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The ENST00000301067.12(KMT2D):c.1940delC(p.Pro647HisfsTer283) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,024,634 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 28)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
KMT2D
ENST00000301067.12 frameshift
ENST00000301067.12 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.50
Publications
12 publications found
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]
KMT2D Gene-Disease associations (from GenCC):
- choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndromeInheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, G2P
- Kabuki syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
- branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndromeInheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Kabuki syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 12-49051742-TG-T is Pathogenic according to our data. Variant chr12-49051742-TG-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 547404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: ENST00000301067.12. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| KMT2D | NM_003482.4 | MANE Select | c.1940delC | p.Pro647HisfsTer283 | frameshift | Exon 11 of 55 | NP_003473.3 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| KMT2D | ENST00000301067.12 | TSL:5 MANE Select | c.1940delC | p.Pro647HisfsTer283 | frameshift | Exon 11 of 55 | ENSP00000301067.7 | ||
| KMT2D | ENST00000683543.2 | c.1940delC | p.Pro647HisfsTer283 | frameshift | Exon 11 of 56 | ENSP00000506726.1 | |||
| KMT2D | ENST00000685166.1 | c.1940delC | p.Pro647HisfsTer283 | frameshift | Exon 10 of 54 | ENSP00000509386.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
28
GnomAD4 exome AF: 0.0000107 AC: 11AN: 1024634Hom.: 0 Cov.: 35 AF XY: 0.0000117 AC XY: 6AN XY: 514508 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
11
AN:
1024634
Hom.:
Cov.:
35
AF XY:
AC XY:
6
AN XY:
514508
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
23238
American (AMR)
AF:
AC:
0
AN:
37904
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
16426
East Asian (EAS)
AF:
AC:
0
AN:
18716
South Asian (SAS)
AF:
AC:
0
AN:
78216
European-Finnish (FIN)
AF:
AC:
1
AN:
32952
Middle Eastern (MID)
AF:
AC:
0
AN:
4206
European-Non Finnish (NFE)
AF:
AC:
9
AN:
774462
Other (OTH)
AF:
AC:
1
AN:
38514
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.230
Heterozygous variant carriers
0
2
4
7
9
11
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
28
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
2
-
-
not provided (2)
1
-
-
Kabuki syndrome 1 (1)
1
-
-
Lung cancer (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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
Publications
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