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-G
• chrX-45069832-C-T

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:6 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6A	NM_001291415.2	c.2333C>A	p.Thr778Lys	missense_variant	Exon 18 of 30	ENST00000611820.5	NP_001278344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5	c.2333C>A	p.Thr778Lys	missense_variant	Exon 18 of 30	1	NM_001291415.2	ENSP00000483595.2

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

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Aug 01, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jul 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Kabuki syndrome 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;.;T;T
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.48	T;T;T;T;T
MetaRNN	Benign	0.0031	T;T;T;T;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;T;T;T;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;