chr12-49026295-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003482.4(KMT2D):​c.15671G>A​(p.Arg5224His) variant causes a missense change. The variant allele was found at a frequency of 0.000445 in 1,611,872 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5224C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00044 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00045 ( 5 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

1
10
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: 3.94

Publications

11 publications found
Variant links:
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 syndrome
    Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, G2P
  • Kabuki syndrome 1
    Inheritance: 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 syndrome
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • Kabuki syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0128855705).
BP6
Variant 12-49026295-C-T is Benign according to our data. Variant chr12-49026295-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134730.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS1
Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00044 (67/152292) while in subpopulation EAS AF = 0.0117 (61/5192). AF 95% confidence interval is 0.00939. There are 1 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KMT2DNM_003482.4 linkc.15671G>A p.Arg5224His missense_variant Exon 49 of 55 ENST00000301067.12 NP_003473.3 O14686-1Q59FG6Q6PIA1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KMT2DENST00000301067.12 linkc.15671G>A p.Arg5224His missense_variant Exon 49 of 55 5 NM_003482.4 ENSP00000301067.7 O14686-1

Frequencies

GnomAD3 genomes
AF:
0.000440
AC:
67
AN:
152174
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.0117
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000983
AC:
245
AN:
249238
AF XY:
0.000880
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000397
Gnomad EAS exome
AF:
0.0126
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000531
Gnomad OTH exome
AF:
0.000992
GnomAD4 exome
AF:
0.000446
AC:
651
AN:
1459580
Hom.:
5
Cov.:
33
AF XY:
0.000419
AC XY:
304
AN XY:
725530
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33452
American (AMR)
AF:
0.00
AC:
0
AN:
44696
Ashkenazi Jewish (ASJ)
AF:
0.000268
AC:
7
AN:
26124
East Asian (EAS)
AF:
0.0142
AC:
564
AN:
39618
South Asian (SAS)
AF:
0.000116
AC:
10
AN:
86234
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53388
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5764
European-Non Finnish (NFE)
AF:
0.0000324
AC:
36
AN:
1110046
Other (OTH)
AF:
0.000531
AC:
32
AN:
60258
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
45
90
134
179
224
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
100
<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
AF:
0.000440
AC:
67
AN:
152292
Hom.:
1
Cov.:
32
AF XY:
0.000497
AC XY:
37
AN XY:
74460
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41552
American (AMR)
AF:
0.00
AC:
0
AN:
15306
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3468
East Asian (EAS)
AF:
0.0117
AC:
61
AN:
5192
South Asian (SAS)
AF:
0.000414
AC:
2
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.523
Heterozygous variant carriers
0
4
8
11
15
19
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
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
Alfa
AF:
0.0000882
Hom.:
0
Bravo
AF:
0.000510
ExAC
AF:
0.00104
AC:
126
Asia WGS
AF:
0.00318
AC:
11
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:2
Aug 02, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 09, 2020
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31935506, 30459467, 29707407) -

Kabuki syndrome 1 Uncertain:1
Mar 04, 2013
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Kabuki syndrome Benign:1
Jan 18, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Other:1
Sep 19, 2013
ITMI
Significance:not provided
Review Status:no classification provided
Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.24
CADD
Uncertain
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.42
T
Eigen
Uncertain
0.22
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.90
D
MetaRNN
Benign
0.013
T
MetaSVM
Uncertain
-0.27
T
MutationAssessor
Uncertain
2.4
M
PhyloP100
3.9
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-4.4
D
REVEL
Uncertain
0.45
Sift
Uncertain
0.0010
D
Polyphen
0.50
P
Vest4
0.61
MVP
0.74
MPC
1.2
ClinPred
0.17
T
GERP RS
4.2
PromoterAI
-0.0080
Neutral
Varity_R
0.38
gMVP
0.73
Mutation Taster
=93/7
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs3782356; hg19: chr12-49420078; COSMIC: COSV104396464; API