17-7846859-TACCACCACCACCACCACCACCACCACC-TACCACCACCACCACC

Variant names:

• chr17-7846859-TACCACCACCACC-T
• rs61462443
• NM_001348716.2:c.780_791delACCACCACCACC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001348716.2(KDM6B):​c.780_791delACCACCACCACC​(p.Pro261_Pro264del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000995 in 1,215,676 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P260P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: KDM6B NM_001348716.2 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.67
• Publications: 8 publications found

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]

KDM6B Gene-Disease associations (from GenCC):

• syndromic intellectual disability

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001348716.2

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348716.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6B	NM_001348716.2	MANE Select	c.780_791delACCACCACCACC	p.Pro261_Pro264del	disruptive_inframe_deletion	Exon 10 of 24	NP_001335645.1	O15054-2
	KDM6B	NM_001080424.2		c.780_791delACCACCACCACC	p.Pro261_Pro264del	disruptive_inframe_deletion	Exon 9 of 22	NP_001073893.1	O15054-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6B	ENST00000448097.7	TSL:5 MANE Select	c.780_791delACCACCACCACC	p.Pro261_Pro264del	disruptive_inframe_deletion	Exon 10 of 24	ENSP00000412513.2	O15054-2
	KDM6B	ENST00000254846.9	TSL:1	c.780_791delACCACCACCACC	p.Pro261_Pro264del	disruptive_inframe_deletion	Exon 9 of 22	ENSP00000254846.5	O15054-1
	KDM6B	ENST00000911119.1		c.780_791delACCACCACCACC	p.Pro261_Pro264del	disruptive_inframe_deletion	Exon 9 of 22	ENSP00000581178.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 7 AN: 118288 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000238

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000516

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 114 AN: 1097388 Hom.: 1 AF XY: 0.000106 AC XY: 59 AN XY: 554582

African (AFR) AF: 0.0000391 AC: 1 AN: 25588

American (AMR) AF: 0.0000777 AC: 3 AN: 38596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22354

East Asian (EAS) AF: 0.000225 AC: 8 AN: 35632

South Asian (SAS) AF: 0.000106 AC: 8 AN: 75534

European-Finnish (FIN) AF: 0.000139 AC: 5 AN: 35914

Middle Eastern (MID) AF: 0.000561 AC: 2 AN: 3566

European-Non Finnish (NFE) AF: 0.000106 AC: 86 AN: 812252

Other (OTH) AF: 0.0000209 AC: 1 AN: 47952

GnomAD4 genome AF: 0.0000592 AC: 7 AN: 118288 Hom.: 0 Cov.: 0 AF XY: 0.0000722 AC XY: 4 AN XY: 55438

African (AFR) AF: 0.000104 AC: 3 AN: 28924

American (AMR) AF: 0.00 AC: 0 AN: 11668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3118

East Asian (EAS) AF: 0.000238 AC: 1 AN: 4194

South Asian (SAS) AF: 0.00 AC: 0 AN: 3612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000516 AC: 3 AN: 58168

Other (OTH) AF: 0.00 AC: 0 AN: 1512

Alfa AF: 0.00 Hom.: 2265

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=194/6	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs61462443; hg19: chr17-7750177;