NM_003482.4:c.6594delC
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003482.4(KMT2D):c.6594delC(p.Tyr2199IlefsTer65) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,366,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 7.3e-7 ( 0 hom. )
Consequence
KMT2D
NM_003482.4 frameshift
NM_003482.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.218
Publications
0 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine, ClinGen
- 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 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 12-49041175-AG-A is Pathogenic according to our data. Variant chr12-49041175-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 531891.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_003482.4. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| KMT2D | TSL:5 MANE Select | c.6594delC | p.Tyr2199IlefsTer65 | frameshift | Exon 32 of 55 | ENSP00000301067.7 | O14686-1 | ||
| KMT2D | c.6594delC | p.Tyr2199IlefsTer65 | frameshift | Exon 32 of 56 | ENSP00000506726.1 | A0A804HHR9 | |||
| KMT2D | c.6603delC | p.Tyr2202IlefsTer65 | frameshift | Exon 31 of 54 | ENSP00000509386.1 | O14686-3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 7.32e-7 AC: 1AN: 1366464Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 670282 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1366464
Hom.:
Cov.:
35
AF XY:
AC XY:
0
AN XY:
670282
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:
30176
American (AMR)
AF:
AC:
0
AN:
28372
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
19792
East Asian (EAS)
AF:
AC:
0
AN:
38908
South Asian (SAS)
AF:
AC:
0
AN:
70208
European-Finnish (FIN)
AF:
AC:
1
AN:
49474
Middle Eastern (MID)
AF:
AC:
0
AN:
5294
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1068120
Other (OTH)
AF:
AC:
0
AN:
56120
⚠️ 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: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Kabuki syndrome (1)
1
-
-
KMT2D-related disorder (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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