17-7846859-T-TACCACCACCACCACCACCACC

Variant names:

• chr17-7846859-T-TACCACCACCACCACCACCACC
• rs61462443
• NM_001348716.2:c.771_791dupACCACCACCACCACCACCACC

Variant summary

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

The NM_001348716.2(KDM6B):​c.771_791dupACCACCACCACCACCACCACC​(p.Pro258_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 0.0000292 in 1,097,534 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 INS_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.

• Frequency:
  • Genomes: 𝑓 0.000051 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KDM6B NM_001348716.2 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.250
• 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.771_791dupACCACCACCACCACCACCACC	p.Pro258_Pro264dup	disruptive_inframe_insertion	Exon 10 of 24	ENST00000448097.7	NP_001335645.1
KDM6B	NM_001080424.2	c.771_791dupACCACCACCACCACCACCACC	p.Pro258_Pro264dup	disruptive_inframe_insertion	Exon 9 of 22		NP_001073893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6B	ENST00000448097.7	c.771_791dupACCACCACCACCACCACCACC	p.Pro258_Pro264dup	disruptive_inframe_insertion	Exon 10 of 24	5	NM_001348716.2	ENSP00000412513.2
KDM6B	ENST00000254846.9	c.771_791dupACCACCACCACCACCACCACC	p.Pro258_Pro264dup	disruptive_inframe_insertion	Exon 9 of 22	1		ENSP00000254846.5
KDM6B	ENST00000570632.1	c.711+138_711+158dupACCACCACCACCACCACCACC		intron_variant	Intron 7 of 8	5		ENSP00000458445.1

Frequencies

GnomAD3 genomes AF: 0.0000507 AC: 6 AN: 118294 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000691

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: 0.0000292 AC: 32 AN: 1097534 Hom.: 0 Cov.: 43 AF XY: 0.0000415 AC XY: 23 AN XY: 554644

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25588

American (AMR) AF: 0.0000777 AC: 3 AN: 38602

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

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35632

South Asian (SAS) AF: 0.000146 AC: 11 AN: 75534

European-Finnish (FIN) AF: 0.0000278 AC: 1 AN: 35930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3566

European-Non Finnish (NFE) AF: 0.0000160 AC: 13 AN: 812368

Other (OTH) AF: 0.0000626 AC: 3 AN: 47960

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000119349), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000507 AC: 6 AN: 118356 Hom.: 0 Cov.: 0 AF XY: 0.0000540 AC XY: 3 AN XY: 55512

African (AFR) AF: 0.0000689 AC: 2 AN: 29016

American (AMR) AF: 0.00 AC: 0 AN: 11684

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4180

South Asian (SAS) AF: 0.000278 AC: 1 AN: 3594

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.0000516 AC: 3 AN: 58166

Other (OTH) AF: 0.00 AC: 0 AN: 1528

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.25
Mutation Taster		=89/11	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;