rs200602649

Variant names:

• chrX-45037659-A-G
• rs200602649
• NM_001291415.2:c.624A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-45037659-A-G
• chrX-45037659-A-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001291415.2(KDM6A):​c.624A>G​(p.Gln208Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,203,545 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000024 (0 hom. 7 hem.)
• Consequence: KDM6A NM_001291415.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.172
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant X-45037659-A-G is Benign according to our data. Variant chrX-45037659-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.172 with no splicing effect.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	NM_001291415.2	MANE Select	c.624A>G	p.Gln208Gln	synonymous	Exon 8 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.624A>G	p.Gln208Gln	synonymous	Exon 8 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.624A>G	p.Gln208Gln	synonymous	Exon 8 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.624A>G	p.Gln208Gln	synonymous	Exon 8 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.624A>G	p.Gln208Gln	synonymous	Exon 8 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.624A>G	p.Gln208Gln	synonymous	Exon 8 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.0000447 AC: 5 AN: 111838 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000975

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000383 AC: 7 AN: 182783 AF XY: 0.0000445

Gnomad AFR exome AF: 0.0000762

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: 0.0000733

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000238 AC: 26 AN: 1091657 Hom.: 0 Cov.: 27 AF XY: 0.0000196 AC XY: 7 AN XY: 357547

African (AFR) AF: 0.0000380 AC: 1 AN: 26285

American (AMR) AF: 0.0000284 AC: 1 AN: 35189

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19329

East Asian (EAS) AF: 0.00 AC: 0 AN: 30090

South Asian (SAS) AF: 0.00 AC: 0 AN: 53944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40113

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4113

European-Non Finnish (NFE) AF: 0.0000251 AC: 21 AN: 836710

Other (OTH) AF: 0.0000654 AC: 3 AN: 45884

GnomAD4 genome AF: 0.0000447 AC: 5 AN: 111888 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34066

African (AFR) AF: 0.0000973 AC: 3 AN: 30828

American (AMR) AF: 0.00 AC: 0 AN: 10503

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.00 AC: 0 AN: 2714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53196

Other (OTH) AF: 0.00 AC: 0 AN: 1521

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.1
DANN	Benign	0.30
PhyloP100		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs200602649; hg19: chrX-44896904; COSMIC: COSV104429243;