rs587778423

Variant names:

• chrX-45051714-A-G
• rs587778423
• NM_001291415.2:c.660A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-45051714-A-G
• chrX-45051714-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001291415.2(KDM6A):​c.660A>G​(p.Lys220Lys) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000105 in 1,146,599 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000068 (0 hom. 2 hem.)
• Consequence: KDM6A NM_001291415.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.28
• 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: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-45051714-A-G is Benign according to our data. Variant chrX-45051714-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2885550.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00000677 (7/1034570) while in subpopulation AFR AF = 0.000238 (6/25187). AF 95% confidence interval is 0.000103. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	NM_001291415.2	MANE Select	c.660A>G	p.Lys220Lys	synonymous	Exon 9 of 30	NP_001278344.1
	KDM6A	NM_001419809.1		c.660A>G	p.Lys220Lys	synonymous	Exon 9 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.660A>G	p.Lys220Lys	synonymous	Exon 9 of 30	NP_001406739.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.660A>G	p.Lys220Lys	synonymous	Exon 9 of 30	ENSP00000483595.2
	KDM6A	ENST00000382899.9	TSL:1	c.660A>G	p.Lys220Lys	synonymous	Exon 9 of 29	ENSP00000372355.6
	KDM6A	ENST00000377967.9	TSL:1	c.660A>G	p.Lys220Lys	synonymous	Exon 9 of 29	ENSP00000367203.4

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 112029 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000116 AC: 2 AN: 172124 AF XY: 0.00

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000677 AC: 7 AN: 1034570 Hom.: 0 Cov.: 21 AF XY: 0.00000627 AC XY: 2 AN XY: 318728

African (AFR) AF: 0.000238 AC: 6 AN: 25187

American (AMR) AF: 0.00 AC: 0 AN: 34310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18757

East Asian (EAS) AF: 0.00 AC: 0 AN: 29861

South Asian (SAS) AF: 0.00 AC: 0 AN: 51405

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40347

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3089

European-Non Finnish (NFE) AF: 0.00000127 AC: 1 AN: 787653

Other (OTH) AF: 0.00 AC: 0 AN: 43961

GnomAD4 genome AF: 0.0000446 AC: 5 AN: 112029 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34183

African (AFR) AF: 0.000162 AC: 5 AN: 30805

American (AMR) AF: 0.00 AC: 0 AN: 10574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.00 AC: 0 AN: 2709

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53233

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kabuki syndrome 2 Benign:1

Apr 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.2
DANN	Benign	0.71
PhyloP100		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs587778423; hg19: chrX-44910959;