chrX-45069832-C-T

Variant names:

• chrX-45069832-C-T
• rs2230018
• NM_001291415.2:c.2333C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001291415.2(KDM6A):​c.2333C>T​(p.Thr778Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,208,747 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 114 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T778K) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.00026 (0 hom. 109 hem.)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.985
• Publications: 44 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03868887).
• BP6: Variant X-45069832-C-T is Benign according to our data. Variant chrX-45069832-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 379452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000198 (22/111262) while in subpopulation SAS AF = 0.000764 (2/2618). AF 95% confidence interval is 0.000204. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 22 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.2333C>T	p.Thr778Met	missense	Exon 18 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.2333C>T	p.Thr778Met	missense	Exon 18 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.2231C>T	p.Thr744Met	missense	Exon 17 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.2333C>T	p.Thr778Met	missense	Exon 18 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.2198C>T	p.Thr733Met	missense	Exon 17 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.2177C>T	p.Thr726Met	missense	Exon 17 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.000198 AC: 22 AN: 111205 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000953

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000762

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000321

Gnomad OTH AF: 0.000669

GnomAD2 exomes AF: 0.000220 AC: 40 AN: 181656 AF XY: 0.000256

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000220

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.000146

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.000262 AC: 287 AN: 1097485 Hom.: 0 Cov.: 32 AF XY: 0.000300 AC XY: 109 AN XY: 362879

African (AFR) AF: 0.00 AC: 0 AN: 26392

American (AMR) AF: 0.000341 AC: 12 AN: 35154

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19384

East Asian (EAS) AF: 0.0000994 AC: 3 AN: 30168

South Asian (SAS) AF: 0.000481 AC: 26 AN: 54100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40484

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4133

European-Non Finnish (NFE) AF: 0.000269 AC: 226 AN: 841600

Other (OTH) AF: 0.000304 AC: 14 AN: 46070

GnomAD4 genome AF: 0.000198 AC: 22 AN: 111262 Hom.: 0 Cov.: 22 AF XY: 0.000150 AC XY: 5 AN XY: 33444

African (AFR) AF: 0.0000326 AC: 1 AN: 30686

American (AMR) AF: 0.0000952 AC: 1 AN: 10502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3464

South Asian (SAS) AF: 0.000764 AC: 2 AN: 2618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000321 AC: 17 AN: 52969

Other (OTH) AF: 0.000660 AC: 1 AN: 1515

Alfa AF: 0.0000106 Hom.: 11077

Bravo AF: 0.000208

ExAC AF: 0.000181 AC: 22

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.018
DANN	Benign	0.84
DEOGEN2	Benign	0.015	T
FATHMM_MKL	Benign	0.078	N
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.98
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.81	N
REVEL	Benign	0.062
Sift	Benign	0.14	T
Sift4G	Benign	0.090	T
Polyphen		0.65	P
Vest4		0.052
MVP		0.19
MPC		0.11
ClinPred		0.0066	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.041
gMVP		0.25
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2230018; hg19: chrX-44929077;