11-67228119-G-C

Variant names:

• chr11-67228119-G-C
• rs201937858
• NM_012308.3:c.1040G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012308.3(KDM2A):​c.1040G>C​(p.Arg347Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. R347H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDM2A NM_012308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.00
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27842593).

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.1040G>C	p.Arg347Pro	missense	Exon 11 of 21	NP_036440.1	Q9Y2K7-1
	KDM2A	NR_027473.2		n.1910G>C		non_coding_transcript_exon	Exon 11 of 21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM2A	ENST00000529006.7	TSL:1 MANE Select	c.1040G>C	p.Arg347Pro	missense	Exon 11 of 21	ENSP00000432786.1	Q9Y2K7-1
	KDM2A	ENST00000308783.9	TSL:1	c.989G>C	p.Arg330Pro	missense	Exon 11 of 21	ENSP00000309302.6	I3VM54
	KDM2A	ENST00000398645.6	TSL:1	c.1040G>C	p.Arg347Pro	missense	Exon 11 of 21	ENSP00000381640.2	Q9Y2K7-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.069	T
Polyphen		0.78	P
Vest4		0.47
MutPred		0.52		Loss of catalytic residue at R347 (P = 0.0317)
MVP		0.32
MPC		1.4
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.90
gMVP		0.92
Mutation Taster		=69/31	polymorphism

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

dbSNP: rs201937858; hg19: chr11-66995590;