rs182572555
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2
The NM_170606.3(KMT2C):c.13522C>T(p.Pro4508Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,614,232 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00045 ( 1 hom., cov: 33)
Exomes 𝑓: 0.000055 ( 0 hom. )
Consequence
KMT2C
NM_170606.3 missense
NM_170606.3 missense
Scores
3
8
6
Clinical Significance
Conservation
PhyloP100: 10.0
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 Benign. Variant got -13 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, KMT2C
BP4
?
Computational evidence support a benign effect (MetaRNN=0.114400625).
BP6
?
Variant 7-152148405-G-A is Benign according to our data. Variant chr7-152148405-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
?
High AC in GnomAd at 69 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KMT2C | NM_170606.3 | c.13522C>T | p.Pro4508Ser | missense_variant | 52/59 | ENST00000262189.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KMT2C | ENST00000262189.11 | c.13522C>T | p.Pro4508Ser | missense_variant | 52/59 | 1 | NM_170606.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000453 AC: 69AN: 152220Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.000223 AC: 56AN: 251222Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135752
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GnomAD4 exome AF: 0.0000554 AC: 81AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35AN XY: 727248
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GnomAD4 genome ? AF: 0.000453 AC: 69AN: 152338Hom.: 1 Cov.: 33 AF XY: 0.000725 AC XY: 54AN XY: 74492
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ClinVar
Significance: Likely benign
Submissions summary: Benign:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The KMT2C p.P4508S variant was not identified in the literature but was identified in dbSNP (ID: rs182572555) and ClinVar (submitted by ITMI, no classification provided). The variant was identified in control databases in 58 of 282632 chromosomes at a frequency of 0.0002052, and was observed at the highest frequency in the Latino population in 53 of 35436 chromosomes (freq: 0.001496) (Genome Aggregation Database March 6, 2019, v2.1.1). This frequency is greater than expected for the rare, autosomal dominant Kleefstra syndrome 2 associated with KMT2C variants. The p.P4508 residue is conserved in mammals and more distantly related organisms however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
KMT2C-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 01, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D
REVEL
Uncertain
Sift
Benign
T;.;T
Polyphen
D;D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at