dbSNP rs587778423: KDM6A:p.Lys220Lys (chrX-45051714-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.28

Publications

1 publications found

Variant links:

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

KDM6A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6A	NM_001291415.2 link	c.660A>G	p.Lys220Lys	synonymous_variant	Exon 9 of 30	ENST00000611820.5	NP_001278344.1	A0A087X0R0B7ZKN5Q86TD1B7ZKN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5 link	c.660A>G	p.Lys220Lys	synonymous_variant	Exon 9 of 30	1	NM_001291415.2	ENSP00000483595.2		A0A087X0R0

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112029

Hom.:

Cov.:

show subpopulations

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:

AN:

172124

AF XY:

0.00

show subpopulations

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:

AN:

1034570

Hom.:

Cov.:

AF XY:

0.00000627

AC XY:

AN XY:

318728

show subpopulations

African (AFR)

AF:

0.000238

AC:

AN:

25187

American (AMR)

AF:

0.00

AC:

AN:

34310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18757

East Asian (EAS)

AF:

0.00

AC:

AN:

29861

South Asian (SAS)

AF:

0.00

AC:

AN:

51405

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40347

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3089

European-Non Finnish (NFE)

AF:

0.00000127

AC:

AN:

787653

Other (OTH)

AF:

0.00

AC:

AN:

43961

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000446

AC:

AN:

112029

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34183

show subpopulations

African (AFR)

AF:

0.000162

AC:

AN:

30805

American (AMR)

AF:

0.00

AC:

AN:

10574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2658

East Asian (EAS)

AF:

0.00

AC:

AN:

3576

South Asian (SAS)

AF:

0.00

AC:

AN:

2709

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53233

Other (OTH)

AF:

0.00

AC:

AN:

1505

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.2

(source)

DANN

Benign

0.71

PhyloP100

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over