Genetic Variant NM_001291415.2:c.1999C>G (chrX-45063737-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001291415.2(KDM6A):c.1999C>G(p.Leu667Val) variant causes a missense change. The variant allele was found at a frequency of 0.00136 in 1,205,284 control chromosomes in the GnomAD database, including 13 homozygotes. There are 397 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L667F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0066 ( 6 hom., 187 hem., cov: 22)

Exomes 𝑓: 0.00082 ( 7 hom. 210 hem. )

Consequence

KDM6A
NM_001291415.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 4.09

Publications

14 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012268305).

BP6

Variant X-45063737-C-G is Benign according to our data. Variant chrX-45063737-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00658 (736/111922) while in subpopulation AFR AF = 0.0231 (711/30741). AF 95% confidence interval is 0.0217. There are 6 homozygotes in GnomAd4. There are 187 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 736 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KDM6A	NM_001291415.2	MANE Select	c.1999C>G	p.Leu667Val	missense	Exon 17 of 30	NP_001278344.1	A0A087X0R0
KDM6A	NM_001419809.1		c.1999C>G	p.Leu667Val	missense	Exon 17 of 31	NP_001406738.1
KDM6A	NM_001419810.1		c.1897C>G	p.Leu633Val	missense	Exon 16 of 30	NP_001406739.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.1999C>G	p.Leu667Val	missense	Exon 17 of 30	ENSP00000483595.2	A0A087X0R0
KDM6A	ENST00000382899.9	TSL:1	c.1864C>G	p.Leu622Val	missense	Exon 16 of 29	ENSP00000372355.6	F8W8R6
KDM6A	ENST00000377967.9	TSL:1	c.1843C>G	p.Leu615Val	missense	Exon 16 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes

AF:

0.00654

AC:

732

AN:

111870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0230

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00152

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:

0.0000564

Gnomad OTH

AF:

0.00399

GnomAD2 exomes

AF:

0.00184

AC:

317

AN:

172315

AF XY:

0.000951

show subpopulations

Gnomad AFR exome

AF:

0.0231

Gnomad AMR exome

AF:

0.000943

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000132

Gnomad OTH exome

AF:

0.000461

GnomAD4 exome

AF:

0.000822

AC:

899

AN:

1093362

Hom.:

Cov.:

AF XY:

0.000585

AC XY:

210

AN XY:

359120

show subpopulations

African (AFR)

AF:

0.0253

AC:

667

AN:

26319

American (AMR)

AF:

0.00106

AC:

AN:

34774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19324

East Asian (EAS)

AF:

0.00

AC:

AN:

30080

South Asian (SAS)

AF:

0.0000749

AC:

AN:

53396

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40227

Middle Eastern (MID)

AF:

0.00242

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.000119

AC:

100

AN:

839172

Other (OTH)

AF:

0.00176

AC:

AN:

45937

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

137

183

229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00658

AC:

736

AN:

111922

Hom.:

Cov.:

AF XY:

0.00548

AC XY:

187

AN XY:

34104

show subpopulations

African (AFR)

AF:

0.0231

AC:

711

AN:

30741

American (AMR)

AF:

0.00151

AC:

AN:

10567

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3570

South Asian (SAS)

AF:

0.00

AC:

AN:

2711

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000564

AC:

AN:

53193

Other (OTH)

AF:

0.00394

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00269

Hom.:

Bravo

AF:

0.00739

ESP6500AA

AF:

0.0211

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00198

AC:

240

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (3)

Kabuki syndrome 2 (1)

KDM6A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.013

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.74

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.81

PhyloP100

4.1

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.7

REVEL

Benign

0.072

Sift

Benign

0.033

Sift4G

Benign

0.52

Polyphen

0.020

Vest4

0.19

MVP

0.38

MPC

0.11

ClinPred

0.0081

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.087

gMVP

0.43

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over