12-121439935-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_032590.5(KDM2B):c.3751G>A(p.Val1251Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000458 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: KDM2B NM_032590.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

Genes affected

KDM2B (HGNC:13610): (lysine demethylase 2B) 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. Multiple alternatively spliced transcript variants have been found for this gene, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KDM2B
• BP4: Computational evidence support a benign effect (MetaRNN=0.039637).
• BS2: High AC in GnomAd at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM2B	NM_032590.5	c.3751G>A	p.Val1251Ile	missense_variant	22/23	ENST00000377071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM2B	ENST00000377071.9	c.3751G>A	p.Val1251Ile	missense_variant	22/23	1	NM_032590.5	P1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000280 AC: 70 AN: 249608 Hom.: 0 AF XY: 0.000310 AC XY: 42 AN XY: 135384

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000450

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000473 AC: 692 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.000472 AC XY: 343 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000542

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74330

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000516 Hom.: 0

Bravo AF: 0.000359

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000468 AC: 4

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2022

The c.3751G>A (p.V1251I) alteration is located in exon 22 (coding exon 22) of the KDM2B gene. This alteration results from a G to A substitution at nucleotide position 3751, causing the valine (V) at amino acid position 1251 to be replaced by an isoleucine (I). 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	Benign	0.076
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	21
Dann	Benign	0.97
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.040	T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.11	N;N;N
REVEL	Benign	0.058
Sift	Benign	0.76	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	.;.;B
Vest4		0.28
MVP		0.15
MPC		0.52
ClinPred		0.038	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs200642027; hg19: chr12-121877738; COSMIC: COSV105316155; COSMIC: COSV105316155;