NM_012308.3:c.704C>T

Variant names:

• chr11-67217747-C-T
• NM_012308.3:c.704C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_012308.3(KDM2A):​c.704C>T​(p.Pro235Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDM2A NM_012308.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.55
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 11-67217747-C-T is Pathogenic according to our data. Variant chr11-67217747-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3778805.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012308.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM2A	NM_012308.3	MANE Select	c.704C>T	p.Pro235Leu	missense	Exon 9 of 21	NP_036440.1	Q9Y2K7-1
	KDM2A	NR_027473.2		n.1574C>T		non_coding_transcript_exon	Exon 9 of 21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM2A	ENST00000529006.7	TSL:1 MANE Select	c.704C>T	p.Pro235Leu	missense	Exon 9 of 21	ENSP00000432786.1	Q9Y2K7-1
	KDM2A	ENST00000308783.9	TSL:1	c.653C>T	p.Pro218Leu	missense	Exon 9 of 21	ENSP00000309302.6	I3VM54
	KDM2A	ENST00000398645.6	TSL:1	c.704C>T	p.Pro235Leu	missense	Exon 9 of 21	ENSP00000381640.2	Q9Y2K7-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	KDM2A-related neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-9.4	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.59		Loss of catalytic residue at P235 (P = 0.0228)
MVP		0.91
MPC		2.8
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		1.0
Mutation Taster		=40/60	disease causing

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

Other links and lift over

hg19: chr11-66985218; COSMIC: COSV101284572; COSMIC: COSV101284572;