chr12-49040404-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_003482.4(KMT2D):​c.7366C>T​(p.Arg2456Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000179 in 1,563,524 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

6
8
4

Clinical Significance

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

Conservation

PhyloP100: 4.41
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.17305553).
BP6
Variant 12-49040404-G-A is Benign according to our data. Variant chr12-49040404-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547444.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS2
High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KMT2DNM_003482.4 linkc.7366C>T p.Arg2456Cys missense_variant 32/55 ENST00000301067.12 NP_003473.3 O14686-1Q59FG6Q6PIA1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KMT2DENST00000301067.12 linkc.7366C>T p.Arg2456Cys missense_variant 32/555 NM_003482.4 ENSP00000301067.7 O14686-1

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.0110
Gnomad AMR
AF:
0.00
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
GnomAD3 exomes
AF:
0.00000962
AC:
2
AN:
207828
Hom.:
0
AF XY:
0.00000897
AC XY:
1
AN XY:
111502
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000458
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000104
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000113
AC:
16
AN:
1411330
Hom.:
0
Cov.:
35
AF XY:
0.0000100
AC XY:
7
AN XY:
696580
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000259
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000255
Gnomad4 SAS exome
AF:
0.0000384
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000101
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152194
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000982
ExAC
AF:
0.00000828
AC:
1

ClinVar

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

Submissions by phenotype

Kabuki syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Kabuki syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 27, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.62
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Benign
0.23
T
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.94
D
M_CAP
Pathogenic
0.71
D
MetaRNN
Benign
0.17
T
MetaSVM
Uncertain
0.37
D
MutationAssessor
Benign
1.1
L
PrimateAI
Pathogenic
0.81
D
PROVEAN
Uncertain
-4.4
D
REVEL
Uncertain
0.54
Sift
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.57
MutPred
0.21
Gain of glycosylation at S2459 (P = 0.0696);
MVP
0.54
MPC
0.76
ClinPred
0.93
D
GERP RS
5.2
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
3.4
Varity_R
0.33
gMVP
0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754060706; hg19: chr12-49434187; COSMIC: COSV56430524; COSMIC: COSV56430524; API