X-44873590-TGCCGCCGCC-TGCCGCCGCCGCC

Variant names:

• chrX-44873590-T-TGCC
• rs797044622
• NM_001291415.2:c.48_50dupCGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001291415.2(KDM6A):​c.48_50dupCGC​(p.Ala17dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00113 in 1,203,989 control chromosomes in the GnomAD database, including 9 homozygotes. There are 352 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (5 hom., 161 hem., cov: 23)
  • Exomes 𝑓: 0.00066 (4 hom. 191 hem.)
• Consequence: KDM6A NM_001291415.2 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.02
• Publications: 1 publications found

Genes affected

KDM6A (HGNC:12637): (lysine demethylase 6A) This gene is located on the X chromosome and is the corresponding locus to a Y-linked gene which encodes a tetratricopeptide repeat (TPR) protein. The encoded protein of this gene contains a JmjC-domain and catalyzes the demethylation of tri/dimethylated histone H3. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2014]

KDM6A Gene-Disease associations (from GenCC):

• Kabuki syndrome 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001291415.2
• BP6: Variant X-44873590-T-TGCC is Benign according to our data. Variant chrX-44873590-T-TGCC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0058 (642/110759) while in subpopulation AFR AF = 0.0199 (605/30456). AF 95% confidence interval is 0.0186. There are 5 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 642 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291415.2. 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
	KDM6A	NM_001291415.2	MANE Select	c.48_50dupCGC	p.Ala17dup	disruptive_inframe_insertion	Exon 1 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.48_50dupCGC	p.Ala17dup	disruptive_inframe_insertion	Exon 1 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.48_50dupCGC	p.Ala17dup	disruptive_inframe_insertion	Exon 1 of 30	NP_001406739.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.48_50dupCGC	p.Ala17dup	disruptive_inframe_insertion	Exon 1 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.48_50dupCGC	p.Ala17dup	disruptive_inframe_insertion	Exon 1 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.48_50dupCGC	p.Ala17dup	disruptive_inframe_insertion	Exon 1 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.00576 AC: 638 AN: 110711 Hom.: 5 Cov.: 23

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00227

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000171

Gnomad OTH AF: 0.00269

GnomAD2 exomes AF: 0.00151 AC: 249 AN: 165211 AF XY: 0.000860

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000842

Gnomad OTH exome AF: 0.000243

GnomAD4 exome AF: 0.000657 AC: 718 AN: 1093230 Hom.: 4 Cov.: 32 AF XY: 0.000530 AC XY: 191 AN XY: 360198

African (AFR) AF: 0.0210 AC: 553 AN: 26346

American (AMR) AF: 0.00143 AC: 50 AN: 34849

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19307

East Asian (EAS) AF: 0.00 AC: 0 AN: 30088

South Asian (SAS) AF: 0.0000744 AC: 4 AN: 53737

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38847

Middle Eastern (MID) AF: 0.000249 AC: 1 AN: 4017

European-Non Finnish (NFE) AF: 0.0000524 AC: 44 AN: 840236

Other (OTH) AF: 0.00144 AC: 66 AN: 45803

GnomAD4 genome AF: 0.00580 AC: 642 AN: 110759 Hom.: 5 Cov.: 23 AF XY: 0.00482 AC XY: 161 AN XY: 33409

African (AFR) AF: 0.0199 AC: 605 AN: 30456

American (AMR) AF: 0.00227 AC: 24 AN: 10577

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3450

South Asian (SAS) AF: 0.00 AC: 0 AN: 2670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5983

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 208

European-Non Finnish (NFE) AF: 0.000171 AC: 9 AN: 52609

Other (OTH) AF: 0.00265 AC: 4 AN: 1508

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Kabuki syndrome 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0
Mutation Taster		=80/20	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs797044622; hg19: chrX-44732836;