17-7846859-TACCACCACCACCACCACCACCACCACC-TACCACCACCACCACCACCACC

Variant names:

• chr17-7846859-TACCACC-T
• rs61462443
• NM_001348716.2:c.786_791delACCACC

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.786_791delACCACC​(p.Pro263_Pro264del) variant causes a disruptive inframe deletion change. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P262P) has been classified as Likely 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:6
• 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: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• 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-TACCACC-T is Benign according to our data. Variant chr17-7846859-TACCACC-T is described in ClinVar as Benign. ClinVar VariationId is 218502.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.786_791delACCACC	p.Pro263_Pro264del	disruptive_inframe_deletion	Exon 10 of 24	NP_001335645.1	O15054-2
	KDM6B	NM_001080424.2		c.786_791delACCACC	p.Pro263_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.786_791delACCACC	p.Pro263_Pro264del	disruptive_inframe_deletion	Exon 10 of 24	ENSP00000412513.2	O15054-2
	KDM6B	ENST00000254846.9	TSL:1	c.786_791delACCACC	p.Pro263_Pro264del	disruptive_inframe_deletion	Exon 9 of 22	ENSP00000254846.5	O15054-1
	KDM6B	ENST00000911119.1		c.786_791delACCACC	p.Pro263_Pro264del	disruptive_inframe_deletion	Exon 9 of 22	ENSP00000581178.1

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 8477 AN: 118270 Hom.: 531 Cov.: 0

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

African (AFR) AF: 0.0204 AC: 523 AN: 25586

American (AMR) AF: 0.239 AC: 9237 AN: 38600

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 1023 AN: 22338

East Asian (EAS) AF: 0.185 AC: 6566 AN: 35538

South Asian (SAS) AF: 0.172 AC: 13003 AN: 75532

European-Finnish (FIN) AF: 0.0553 AC: 1988 AN: 35928

Middle Eastern (MID) AF: 0.0432 AC: 154 AN: 3566

European-Non Finnish (NFE) AF: 0.0697 AC: 56611 AN: 812230

Other (OTH) AF: 0.0810 AC: 3882 AN: 47944

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

African (AFR) AF: 0.0250 AC: 725 AN: 29010

American (AMR) AF: 0.184 AC: 2153 AN: 11684

Ashkenazi Jewish (ASJ) AF: 0.0414 AC: 129 AN: 3118

East Asian (EAS) AF: 0.141 AC: 590 AN: 4178

South Asian (SAS) AF: 0.217 AC: 781 AN: 3592

European-Finnish (FIN) AF: 0.0764 AC: 461 AN: 6034

Middle Eastern (MID) AF: 0.0197 AC: 5 AN: 254

European-Non Finnish (NFE) AF: 0.0601 AC: 3498 AN: 58158

Other (OTH) AF: 0.0682 AC: 104 AN: 1526

Alfa AF: 0.0482 Hom.: 2265

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=200/0	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61462443;

hg19: chr17-7750177;

COSMIC: COSV99640789;

COSMIC: COSV99640789;