chr11-67215432-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_012308.3(KDM2A):​c.579C>G​(p.Tyr193*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

KDM2A
NM_012308.3 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.276
Variant links:
Genes affected
KDM2A (HGNC:13606): (lysine demethylase 2A) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains at least six highly degenerated leucine-rich repeats. This family member plays a role in epigenetic silencing. It nucleates at CpG islands and specifically demethylates both mono- and di-methylated lysine-36 of histone H3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-67215432-C-G is Pathogenic according to our data. Variant chr11-67215432-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 3778798.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KDM2ANM_012308.3 linkc.579C>G p.Tyr193* stop_gained Exon 7 of 21 ENST00000529006.7 NP_036440.1 Q9Y2K7-1I3VM53

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KDM2AENST00000529006.7 linkc.579C>G p.Tyr193* stop_gained Exon 7 of 21 1 NM_012308.3 ENSP00000432786.1 Q9Y2K7-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

KDM2A-related neurodevelopmental disorder Pathogenic:1
Jan 20, 2025
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

Criteria applied: PVS1, PS2_MOD, PM2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.97
D
Vest4
0.83
GERP RS
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: chr11-66982903; API