17-7846859-TACCACCACCACCACCACCACCACCACC-TACCACCACCACCACCACC

Variant names:

• chr17-7846859-TACCACCACC-T
• rs61462443
• NM_001348716.2:c.783_791delACCACCACC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BP6_Very_Strong

The NM_001348716.2(KDM6B):​c.783_791delACCACCACC​(p.Pro262_Pro264del) variant causes a disruptive inframe deletion change. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P261P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (61 hom., cov: 0)
  • Exomes 𝑓: 0.027 (316 hom.)
  • Failed GnomAD Quality Control
• Consequence: KDM6B NM_001348716.2 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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: Benign. The variant received -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001348716.2
• BP6: Variant 17-7846859-TACCACCACC-T is Benign according to our data. Variant chr17-7846859-TACCACCACC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1174808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.783_791delACCACCACC	p.Pro262_Pro264del	disruptive_inframe_deletion	Exon 10 of 24	NP_001335645.1	O15054-2
	KDM6B	NM_001080424.2		c.783_791delACCACCACC	p.Pro262_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.783_791delACCACCACC	p.Pro262_Pro264del	disruptive_inframe_deletion	Exon 10 of 24	ENSP00000412513.2	O15054-2
	KDM6B	ENST00000254846.9	TSL:1	c.783_791delACCACCACC	p.Pro262_Pro264del	disruptive_inframe_deletion	Exon 9 of 22	ENSP00000254846.5	O15054-1
	KDM6B	ENST00000911119.1		c.783_791delACCACCACC	p.Pro262_Pro264del	disruptive_inframe_deletion	Exon 9 of 22	ENSP00000581178.1

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 2768 AN: 118276 Hom.: 61 Cov.: 0

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00257

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.00215

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0499

Gnomad MID AF: 0.00362

Gnomad NFE AF: 0.0289

Gnomad OTH AF: 0.0265

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0274 AC: 30036 AN: 1094542 Hom.: 316 AF XY: 0.0261 AC XY: 14453 AN XY: 553030

African (AFR) AF: 0.0154 AC: 395 AN: 25580

American (AMR) AF: 0.0168 AC: 636 AN: 37766

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 413 AN: 22336

East Asian (EAS) AF: 0.000939 AC: 33 AN: 35138

South Asian (SAS) AF: 0.00206 AC: 154 AN: 74746

European-Finnish (FIN) AF: 0.0383 AC: 1374 AN: 35884

Middle Eastern (MID) AF: 0.0107 AC: 38 AN: 3566

European-Non Finnish (NFE) AF: 0.0318 AC: 25824 AN: 811632

Other (OTH) AF: 0.0244 AC: 1169 AN: 47894

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0234 AC: 2770 AN: 118338 Hom.: 61 Cov.: 0 AF XY: 0.0234 AC XY: 1300 AN XY: 55494

African (AFR) AF: 0.0143 AC: 414 AN: 29014

American (AMR) AF: 0.0214 AC: 250 AN: 11682

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 65 AN: 3118

East Asian (EAS) AF: 0.00215 AC: 9 AN: 4180

South Asian (SAS) AF: 0.00250 AC: 9 AN: 3594

European-Finnish (FIN) AF: 0.0499 AC: 301 AN: 6034

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

European-Non Finnish (NFE) AF: 0.0289 AC: 1680 AN: 58156

Other (OTH) AF: 0.0262 AC: 40 AN: 1528

Alfa AF: 0.0298 Hom.: 2265

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	KDM6B-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=196/4	polymorphism (auto)

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; COSMIC: COSV54680564; COSMIC: COSV54680564;