rs2230018

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-45069832-C-A
• chrX-45069832-C-T
• chrX-45069832-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001291415.2(KDM6A):​c.2333C>A​(p.Thr778Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,208,646 control chromosomes in the GnomAD database, including 7,744 homozygotes. There are 51,061 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T778M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (593 hom., 3326 hem., cov: 22)
  • Exomes 𝑓: 0.13 (7151 hom. 47735 hem.)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• 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=0.0030804276).
• BP6: Variant X-45069832-C-A is Benign according to our data. Variant chrX-45069832-C-A is described in ClinVar as Benign. ClinVar VariationId is 134597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

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>A	p.Thr778Lys	missense	Exon 18 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.2333C>A	p.Thr778Lys	missense	Exon 18 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.2231C>A	p.Thr744Lys	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>A	p.Thr778Lys	missense	Exon 18 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.2198C>A	p.Thr733Lys	missense	Exon 17 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.2177C>A	p.Thr726Lys	missense	Exon 17 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.102 AC: 11368 AN: 111179 Hom.: 595 Cov.: 22

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.0349

Gnomad AMR AF: 0.0514

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.0966

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.0951

GnomAD2 exomes AF: 0.134 AC: 24296 AN: 181656 AF XY: 0.137

Gnomad AFR exome AF: 0.0420

Gnomad AMR exome AF: 0.0450

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.385

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.129 AC: 141123 AN: 1097410 Hom.: 7151 Cov.: 32 AF XY: 0.132 AC XY: 47735 AN XY: 362846

African (AFR) AF: 0.0405 AC: 1069 AN: 26390

American (AMR) AF: 0.0443 AC: 1557 AN: 35153

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 2573 AN: 19384

East Asian (EAS) AF: 0.428 AC: 12914 AN: 30164

South Asian (SAS) AF: 0.191 AC: 10352 AN: 54098

European-Finnish (FIN) AF: 0.164 AC: 6658 AN: 40482

Middle Eastern (MID) AF: 0.0975 AC: 403 AN: 4133

European-Non Finnish (NFE) AF: 0.118 AC: 99583 AN: 841539

Other (OTH) AF: 0.131 AC: 6014 AN: 46067

GnomAD4 genome AF: 0.102 AC: 11367 AN: 111236 Hom.: 593 Cov.: 22 AF XY: 0.0995 AC XY: 3326 AN XY: 33434

African (AFR) AF: 0.0428 AC: 1314 AN: 30672

American (AMR) AF: 0.0513 AC: 539 AN: 10502

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 355 AN: 2639

East Asian (EAS) AF: 0.385 AC: 1334 AN: 3463

South Asian (SAS) AF: 0.184 AC: 483 AN: 2618

European-Finnish (FIN) AF: 0.133 AC: 792 AN: 5963

Middle Eastern (MID) AF: 0.0829 AC: 18 AN: 217

European-Non Finnish (NFE) AF: 0.120 AC: 6356 AN: 52961

Other (OTH) AF: 0.100 AC: 152 AN: 1513

Alfa AF: 0.113 Hom.: 11077

Bravo AF: 0.0944

TwinsUK AF: 0.120 AC: 445

ALSPAC AF: 0.115 AC: 333

ESP6500AA AF: 0.0485 AC: 186

ESP6500EA AF: 0.118 AC: 794

ExAC AF: 0.136 AC: 16555

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (5)
-	-	2	not provided (2)
-	-	1	Kabuki syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.028
DANN	Benign	0.85
DEOGEN2	Benign	0.031	T
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.98
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.058
Sift	Benign	0.056	T
Sift4G	Benign	0.69	T
Polyphen		0.046	B
Vest4		0.077
MPC		0.13
ClinPred		0.0066	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.41
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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; COSMIC: COSV65036981;