17-7846859-TACCACCACCACCACCACCACCACC-TACCACCACCACCACCACC

Position:

• chr17-7846859-TACCACCACCACCACCACCACCACC-TACCACCACCACCACCACC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001348716.2(KDM6B):​c.786_791delACCACC​(p.Pro263_Pro264del) variant causes a disruptive inframe deletion change. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (534 hom., cov: 0)
  • Exomes 𝑓: 0.085 (3182 hom.)
  • Failed GnomAD Quality Control
• Consequence: KDM6B NM_001348716.2 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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 Benign. Variant got -8 ACMG points.

• BP6: Variant 17-7846859-TACCACC-T is Benign according to our data. Variant chr17-7846859-TACCACC-T is described in ClinVar as [Benign]. Clinvar id is 218502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7846859-TACCACC-T is described in Lovd as [Likely_benign]. Variant chr17-7846859-TACCACC-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM6B	NM_001348716.2	c.786_791delACCACC	p.Pro263_Pro264del	disruptive_inframe_deletion	10/24	ENST00000448097.7	NP_001335645.1
KDM6B	NM_001080424.2	c.786_791delACCACC	p.Pro263_Pro264del	disruptive_inframe_deletion	9/22		NP_001073893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM6B	ENST00000448097.7	c.786_791delACCACC	p.Pro263_Pro264del	disruptive_inframe_deletion	10/24	5	NM_001348716.2	ENSP00000412513.2
KDM6B	ENST00000254846.9	c.786_791delACCACC	p.Pro263_Pro264del	disruptive_inframe_deletion	9/22	1		ENSP00000254846.5
KDM6B	ENST00000570632.1	c.711+153_711+158delACCACC		intron_variant		5		ENSP00000458445.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 8477 AN: 118270 Hom.: 531 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.0414

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.0764

Gnomad MID AF: 0.0254

Gnomad NFE AF: 0.0602

Gnomad OTH AF: 0.0689

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0847 AC: 92987 AN: 1097262 Hom.: 3182 AF XY: 0.0860 AC XY: 47682 AN XY: 554506

Gnomad4 AFR exome AF: 0.0204

Gnomad4 AMR exome AF: 0.239

Gnomad4 ASJ exome AF: 0.0458

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.0553

Gnomad4 NFE exome AF: 0.0697

Gnomad4 OTH exome AF: 0.0810

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0717 AC: 8487 AN: 118332 Hom.: 534 Cov.: 0 AF XY: 0.0792 AC XY: 4394 AN XY: 55502

Gnomad4 AFR AF: 0.0250

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.0414

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.0764

Gnomad4 NFE AF: 0.0601

Gnomad4 OTH AF: 0.0682

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

May 05, 2015

- -

Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

European Non-Finnish population allele frequency is 18.48% (rs779500270, 1399/23430 alleles, 15 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

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;