17-7846859-TACCACCACCACCACCACCACCACC-TACCACC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001348716.2(KDM6B):c.774_791del(p.Pro259_Pro264del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000126 in 1,215,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: KDM6B NM_001348716.2 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

Genes affected

KDM6B (HGNC:29012): (lysine demethylase 6B) The protein encoded by this gene is a lysine-specific demethylase that specifically demethylates di- or tri-methylated lysine 27 of histone H3 (H3K27me2 or H3K27me3). H3K27 trimethylation is a repressive epigenetic mark controlling chromatin organization and gene silencing. This protein can also demethylate non-histone proteins such as retinoblastoma protein. Through its demethylation actvity this gene influences cellular differentiation and development, tumorigenesis, inflammatory diseases, and neurodegenerative diseases. This protein has two classical nuclear localization signals at its N-terminus. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM6B	NM_001348716.2	c.774_791del	p.Pro259_Pro264del	inframe_deletion	10/24	ENST00000448097.7
KDM6B	NM_001080424.2	c.774_791del	p.Pro259_Pro264del	inframe_deletion	9/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM6B	ENST00000448097.7	c.774_791del	p.Pro259_Pro264del	inframe_deletion	10/24	5	NM_001348716.2	A2
KDM6B	ENST00000254846.9	c.774_791del	p.Pro259_Pro264del	inframe_deletion	9/22	1		P2
KDM6B	ENST00000570632.1	c.711+141_711+158del		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000127 AC: 15 AN: 118292 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000257

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000238

Gnomad SAS AF: 0.000277

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 138 AN: 1097536 Hom.: 0 AF XY: 0.000139 AC XY: 77 AN XY: 554648

Gnomad4 AFR exome AF: 0.0000782

Gnomad4 AMR exome AF: 0.000311

Gnomad4 ASJ exome AF: 0.0000895

Gnomad4 EAS exome AF: 0.000168

Gnomad4 SAS exome AF: 0.000318

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.0000834

GnomAD4 genome AF: 0.000127 AC: 15 AN: 118354 Hom.: 0 Cov.: 0 AF XY: 0.0000901 AC XY: 5 AN XY: 55510

Gnomad4 AFR AF: 0.000138

Gnomad4 AMR AF: 0.000257

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000239

Gnomad4 SAS AF: 0.000278

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

KDM6B-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 13, 2022

The KDM6B c.774_791del18 variant is predicted to result in an in-frame deletion (p.Pro259_Pro264del). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61462443; hg19: chr17-7750177;