11-67246001-C-T

Position:

• chr11-67246001-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012308.3(KDM2A):​c.1850C>T​(p.Ser617Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KDM2A NM_012308.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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]

KDM2A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM2A	NM_012308.3	c.1850C>T	p.Ser617Leu	missense_variant	15/21	ENST00000529006.7	NP_036440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM2A	ENST00000529006.7	c.1850C>T	p.Ser617Leu	missense_variant	15/21	1	NM_012308.3	ENSP00000432786.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.1850C>T (p.S617L) alteration is located in exon 15 (coding exon 14) of the KDM2A gene. This alteration results from a C to T substitution at nucleotide position 1850, causing the serine (S) at amino acid position 617 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	.;T;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.8	L;L;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.97	.;D;.;.
Vest4		0.61
MutPred		0.39		Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);.;.;
MVP		0.68
MPC		1.7
ClinPred		0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.39
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr11-67013472;