chr12-49053059-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003482.4(KMT2D):​c.968G>C​(p.Cys323Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C323Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

KMT2D
NM_003482.4 missense

Scores

14
1
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.59

Publications

2 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KMT2DNM_003482.4 linkc.968G>C p.Cys323Ser missense_variant Exon 9 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.968G>C p.Cys323Ser missense_variant Exon 9 of 55 5 NM_003482.4 ENSP00000301067.7 O14686-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152252
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
33
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152252
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74392
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41458
American (AMR)
AF:
0.0000654
AC:
1
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5208
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68038
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Kabuki syndrome Uncertain:1
Nov 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 323 of the KMT2D protein (p.Cys323Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KMT2D-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KMT2D protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.20
CADD
Benign
22
DANN
Benign
0.78
DEOGEN2
Benign
0.29
T
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Pathogenic
3.0
M
PhyloP100
6.6
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-7.4
D
REVEL
Pathogenic
0.69
Sift
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.84
MutPred
0.77
Gain of disorder (P = 0.0267);
MVP
0.80
MPC
0.23
ClinPred
0.78
D
GERP RS
5.6
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.7
Varity_R
0.84
gMVP
0.86
Mutation Taster
=8/92
disease causing

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: rs78617409; hg19: chr12-49446842; API