rs369684496

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The ENST00000262189.11(KMT2C):​c.14107G>C​(p.Val4703Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4703I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

KMT2C
ENST00000262189.11 missense

Scores

4
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.88
Variant links:
Genes affected
KMT2C (HGNC:13726): (lysine methyltransferase 2C) This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a nuclear protein with an AT hook DNA-binding domain, a DHHC-type zinc finger, six PHD-type zinc fingers, a SET domain, a post-SET domain and a RING-type zinc finger. This protein is a member of the ASC-2/NCOA6 complex (ASCOM), which possesses histone methylation activity and is involved in transcriptional coactivation. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KMT2C. . Gene score misZ 2.1357 (greater than the threshold 3.09). Trascript score misZ 4.2875 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, syndromic intellectual disability, Kleefstra syndrome 2.
BP4
Computational evidence support a benign effect (MetaRNN=0.15424624).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KMT2CNM_170606.3 linkuse as main transcriptc.14107G>C p.Val4703Leu missense_variant 54/59 ENST00000262189.11 NP_733751.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KMT2CENST00000262189.11 linkuse as main transcriptc.14107G>C p.Val4703Leu missense_variant 54/591 NM_170606.3 ENSP00000262189 P2Q8NEZ4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.48
BayesDel_addAF
Uncertain
0.052
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
17
DANN
Benign
0.86
DEOGEN2
Benign
0.14
T;T;.
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.31
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.90
.;D;D
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Benign
-0.58
T
MutationAssessor
Benign
0.97
L;L;.
MutationTaster
Benign
0.54
N;N
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.3
N;.;N
REVEL
Benign
0.19
Sift
Benign
0.18
T;.;T
Sift4G
Benign
0.14
.;.;T
Polyphen
0.30
B;B;.
Vest4
0.20
MutPred
0.31
Gain of disorder (P = 0.1358);Gain of disorder (P = 0.1358);.;
MVP
0.44
MPC
1.4
ClinPred
0.31
T
GERP RS
1.9
Varity_R
0.20
gMVP
0.42

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-151842305; API