12-49039866-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP6_Moderate

The NM_003482.4(KMT2D):ā€‹c.7904G>Cā€‹(p.Arg2635Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2635Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

2
5
11

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.47
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 12-49039866-C-G is Benign according to our data. Variant chr12-49039866-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2054233.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KMT2DNM_003482.4 linkc.7904G>C p.Arg2635Pro 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.7904G>C p.Arg2635Pro missense_variant 32/555 NM_003482.4 ENSP00000301067.7 O14686-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461696
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727126
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Kabuki syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 04, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.030
CADD
Uncertain
23
DANN
Benign
0.94
DEOGEN2
Benign
0.044
T
Eigen
Benign
-0.14
Eigen_PC
Benign
0.065
FATHMM_MKL
Benign
0.58
D
LIST_S2
Benign
0.80
T
M_CAP
Pathogenic
0.39
D
MetaRNN
Uncertain
0.48
T
MetaSVM
Benign
-0.48
T
MutationAssessor
Benign
1.1
L
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-1.1
N
REVEL
Uncertain
0.38
Sift
Uncertain
0.0080
D
Polyphen
0.079
B
Vest4
0.74
MutPred
0.19
Loss of catalytic residue at R2635 (P = 0.0331);
MVP
0.84
MPC
0.26
ClinPred
0.39
T
GERP RS
5.6
Varity_R
0.33
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs200359477; hg19: chr12-49433649; API