17-7846859-TACCACCACCACCACCACCACCACCACC-TACCACCACCACC

Variant names:

• chr17-7846859-TACCACCACCACCACC-T
• rs61462443
• NM_001348716.2:c.777_791delACCACCACCACCACC

Variant summary

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

The NM_001348716.2(KDM6B):​c.777_791delACCACCACCACCACC​(p.Pro260_Pro264del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000133 in 1,215,816 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. P259P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000068 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: KDM6B NM_001348716.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• 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: AD, AR Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6B	NM_001348716.2	c.777_791delACCACCACCACCACC	p.Pro260_Pro264del	disruptive_inframe_deletion	Exon 10 of 24	ENST00000448097.7	NP_001335645.1
KDM6B	NM_001080424.2	c.777_791delACCACCACCACCACC	p.Pro260_Pro264del	disruptive_inframe_deletion	Exon 9 of 22		NP_001073893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6B	ENST00000448097.7	c.777_791delACCACCACCACCACC	p.Pro260_Pro264del	disruptive_inframe_deletion	Exon 10 of 24	5	NM_001348716.2	ENSP00000412513.2
KDM6B	ENST00000254846.9	c.777_791delACCACCACCACCACC	p.Pro260_Pro264del	disruptive_inframe_deletion	Exon 9 of 22	1		ENSP00000254846.5
KDM6B	ENST00000570632.1	c.711+144_711+158delACCACCACCACCACC		intron_variant	Intron 7 of 8	5		ENSP00000458445.1

Frequencies

GnomAD3 genomes AF: 0.0000676 AC: 8 AN: 118286 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000277

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000516

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000140 AC: 154 AN: 1097530 Hom.: 0 AF XY: 0.000121 AC XY: 67 AN XY: 554644

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

American (AMR) AF: 0.0000259 AC: 1 AN: 38604

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

East Asian (EAS) AF: 0.0000561 AC: 2 AN: 35632

South Asian (SAS) AF: 0.000132 AC: 10 AN: 75536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35930

Middle Eastern (MID) AF: 0.00224 AC: 8 AN: 3566

European-Non Finnish (NFE) AF: 0.000154 AC: 125 AN: 812360

Other (OTH) AF: 0.000146 AC: 7 AN: 47960

GnomAD4 genome AF: 0.0000676 AC: 8 AN: 118286 Hom.: 0 Cov.: 0 AF XY: 0.0000902 AC XY: 5 AN XY: 55434

African (AFR) AF: 0.000138 AC: 4 AN: 28920

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

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4194

South Asian (SAS) AF: 0.000277 AC: 1 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: 58170

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

Alfa AF: 0.00 Hom.: 2265

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=191/9	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;