X-44873579-ACCGCCGCCGCTG-ACCGCCGCCGCTGCCGCCGCCGCTG

Variant names:

• chrX-44873579-A-ACCGCCGCCGCTG
• rs749062014
• NM_001291415.2:c.40_51dupGCCGCCGCCGCT

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.40_51dupGCCGCCGCCGCT​(p.Ala14_Ala17dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 1,197,292 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 104 hemizygotes in GnomAD. 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. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00025 (0 hom. 99 hem.)
• Consequence: KDM6A NM_001291415.2 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.977
• Publications: 0 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-44873579-A-ACCGCCGCCGCTG is Benign according to our data. Variant chrX-44873579-A-ACCGCCGCCGCTG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1164597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000159 (17/107232) while in subpopulation EAS AF = 0.000599 (2/3339). AF 95% confidence interval is 0.000149. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 17 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.40_51dupGCCGCCGCCGCT	p.Ala14_Ala17dup	conservative_inframe_insertion	Exon 1 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.40_51dupGCCGCCGCCGCT	p.Ala14_Ala17dup	conservative_inframe_insertion	Exon 1 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.40_51dupGCCGCCGCCGCT	p.Ala14_Ala17dup	conservative_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.40_51dupGCCGCCGCCGCT	p.Ala14_Ala17dup	conservative_inframe_insertion	Exon 1 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.40_51dupGCCGCCGCCGCT	p.Ala14_Ala17dup	conservative_inframe_insertion	Exon 1 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.40_51dupGCCGCCGCCGCT	p.Ala14_Ala17dup	conservative_inframe_insertion	Exon 1 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.000159 AC: 17 AN: 107182 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000195

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000597

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000252

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000119 AC: 19 AN: 160255 AF XY: 0.000162

Gnomad AFR exome AF: 0.000101

Gnomad AMR exome AF: 0.0000765

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000233

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000250 AC: 272 AN: 1090060 Hom.: 0 Cov.: 32 AF XY: 0.000277 AC XY: 99 AN XY: 358010

African (AFR) AF: 0.0000761 AC: 2 AN: 26284

American (AMR) AF: 0.0000581 AC: 2 AN: 34405

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19244

East Asian (EAS) AF: 0.000235 AC: 7 AN: 29816

South Asian (SAS) AF: 0.00 AC: 0 AN: 53437

European-Finnish (FIN) AF: 0.0000520 AC: 2 AN: 38468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3891

European-Non Finnish (NFE) AF: 0.000297 AC: 249 AN: 838872

Other (OTH) AF: 0.000219 AC: 10 AN: 45643

GnomAD4 genome AF: 0.000159 AC: 17 AN: 107232 Hom.: 0 Cov.: 23 AF XY: 0.000160 AC XY: 5 AN XY: 31260

African (AFR) AF: 0.00 AC: 0 AN: 29053

American (AMR) AF: 0.000195 AC: 2 AN: 10261

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2587

East Asian (EAS) AF: 0.000599 AC: 2 AN: 3339

South Asian (SAS) AF: 0.00 AC: 0 AN: 2528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 196

European-Non Finnish (NFE) AF: 0.000252 AC: 13 AN: 51544

Other (OTH) AF: 0.00 AC: 0 AN: 1467

Alfa AF: 0.000261 Hom.: 3

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.98
Mutation Taster		=79/21	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs749062014; hg19: chrX-44732825;