17-7846859-TACCACCACCACCACCACCACCACC-TACCACCACCACCACCACCACCACCACCACCACCACCACC

Position:

• chr17-7846859-TACCACCACCACCACCACCACCACC-TACCACCACCACCACCACCACCACCACCACCACCACCACC

Variant summary

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

The NM_001348716.2(KDM6B):​c.777_791dupACCACCACCACCACC​(p.Pro260_Pro264dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000431 in 1,097,434 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00043 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: KDM6B NM_001348716.2 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.250

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 GnomAdExome4 at 473 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM6B	NM_001348716.2	c.777_791dupACCACCACCACCACC	p.Pro260_Pro264dup	disruptive_inframe_insertion	10/24	ENST00000448097.7	NP_001335645.1
KDM6B	NM_001080424.2	c.777_791dupACCACCACCACCACC	p.Pro260_Pro264dup	disruptive_inframe_insertion	9/22		NP_001073893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM6B	ENST00000448097.7	c.777_791dupACCACCACCACCACC	p.Pro260_Pro264dup	disruptive_inframe_insertion	10/24	5	NM_001348716.2	ENSP00000412513.2
KDM6B	ENST00000254846.9	c.777_791dupACCACCACCACCACC	p.Pro260_Pro264dup	disruptive_inframe_insertion	9/22	1		ENSP00000254846.5
KDM6B	ENST00000570632.1	c.711+144_711+158dupACCACCACCACCACC		intron_variant		5		ENSP00000458445.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 68 AN: 118294 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.000795

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000514

Gnomad ASJ AF: 0.000641

Gnomad EAS AF: 0.00119

Gnomad SAS AF: 0.00277

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000344

Gnomad OTH AF: 0.000661

GnomAD4 exome AF: 0.000431 AC: 473 AN: 1097434 Hom.: 3 Cov.: 43 AF XY: 0.000465 AC XY: 258 AN XY: 554604

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000855

Gnomad4 ASJ exome AF: 0.000403

Gnomad4 EAS exome AF: 0.000702

Gnomad4 SAS exome AF: 0.00127

Gnomad4 FIN exome AF: 0.000195

Gnomad4 NFE exome AF: 0.000321

Gnomad4 OTH exome AF: 0.000542

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000591 AC: 70 AN: 118356 Hom.: 0 Cov.: 0 AF XY: 0.000721 AC XY: 40 AN XY: 55512

Gnomad4 AFR AF: 0.000827

Gnomad4 AMR AF: 0.000514

Gnomad4 ASJ AF: 0.000641

Gnomad4 EAS AF: 0.00120

Gnomad4 SAS AF: 0.00278

Gnomad4 FIN AF: 0.000166

Gnomad4 NFE AF: 0.000361

Gnomad4 OTH AF: 0.000654

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

KDM6B-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2024

The KDM6B c.777_791dup15 variant is predicted to result in an in-frame duplication (p.Pro260_Pro264dup). To our knowledge, this variant has not been reported in the literature or in a large population database, 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;