17-7846859-TACCACCACCACCACCACCACCACC-TACCACCACCACCACCACCACCACCACCACCACCACC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_001348716.2(KDM6B):c.780_791dup(p.Pro261_Pro264dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,097,236 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0019 (9 hom.)
  • Failed GnomAD Quality Control
• Consequence: KDM6B NM_001348716.2 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B: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 -6 ACMG points.

• BP6: Variant 17-7846859-T-TACCACCACCACC is Benign according to our data. Variant chr17-7846859-T-TACCACCACCACC is described in ClinVar as [Likely_benign]. Clinvar id is 3037897.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00188 (2062/1097236) while in subpopulation EAS AF= 0.00907 (323/35624). AF 95% confidence interval is 0.00825. There are 9 homozygotes in gnomad4_exome. There are 1009 alleles in male gnomad4_exome subpopulation. Median coverage is 43. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM6B	NM_001348716.2	c.780_791dup	p.Pro261_Pro264dup	inframe_insertion	10/24	ENST00000448097.7
KDM6B	NM_001080424.2	c.780_791dup	p.Pro261_Pro264dup	inframe_insertion	9/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM6B	ENST00000448097.7	c.780_791dup	p.Pro261_Pro264dup	inframe_insertion	10/24	5	NM_001348716.2	A2
KDM6B	ENST00000254846.9	c.780_791dup	p.Pro261_Pro264dup	inframe_insertion	9/22	1		P2
KDM6B	ENST00000570632.1	c.711+147_711+158dup		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 271 AN: 118286 Hom.: 1 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00214

Gnomad ASJ AF: 0.00481

Gnomad EAS AF: 0.00787

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00167

Gnomad OTH AF: 0.000661

GnomAD4 exome AF: 0.00188 AC: 2062 AN: 1097236 Hom.: 9 Cov.: 43 AF XY: 0.00182 AC XY: 1009 AN XY: 554504

Gnomad4 AFR exome AF: 0.00313

Gnomad4 AMR exome AF: 0.00171

Gnomad4 ASJ exome AF: 0.00407

Gnomad4 EAS exome AF: 0.00907

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00157

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00230 AC: 272 AN: 118348 Hom.: 1 Cov.: 0 AF XY: 0.00211 AC XY: 117 AN XY: 55506

Gnomad4 AFR AF: 0.00314

Gnomad4 AMR AF: 0.00214

Gnomad4 ASJ AF: 0.00481

Gnomad4 EAS AF: 0.00789

Gnomad4 SAS AF: 0.000835

Gnomad4 FIN AF: 0.00116

Gnomad4 NFE AF: 0.00167

Gnomad4 OTH AF: 0.000654

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

KDM6B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 07, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;