Genetic Variant NM_001291415.2:c.39_44dupTGCCGC (chrX-44873584-C-CGCCGCT) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP3

The NM_001291415.2(KDM6A):c.39_44dupTGCCGC(p.Ala14_Ala15dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00000275 in 1,092,458 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A15A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

KDM6A
NM_001291415.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.43

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_001291415.2

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.39_44dupTGCCGC	p.Ala14_Ala15dup	disruptive_inframe_insertion	Exon 1 of 30	NP_001278344.1	A0A087X0R0
KDM6A	NM_001419809.1		c.39_44dupTGCCGC	p.Ala14_Ala15dup	disruptive_inframe_insertion	Exon 1 of 31	NP_001406738.1
KDM6A	NM_001419810.1		c.39_44dupTGCCGC	p.Ala14_Ala15dup	disruptive_inframe_insertion	Exon 1 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.39_44dupTGCCGC	p.Ala14_Ala15dup	disruptive_inframe_insertion	Exon 1 of 30	ENSP00000483595.2	A0A087X0R0
KDM6A	ENST00000382899.9	TSL:1	c.39_44dupTGCCGC	p.Ala14_Ala15dup	disruptive_inframe_insertion	Exon 1 of 29	ENSP00000372355.6	F8W8R6
KDM6A	ENST00000377967.9	TSL:1	c.39_44dupTGCCGC	p.Ala14_Ala15dup	disruptive_inframe_insertion	Exon 1 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111056

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00000609

AC:

AN:

164115

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000142

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1092458

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

359612

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26333

American (AMR)

AF:

0.00

AC:

AN:

34743

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19290

East Asian (EAS)

AF:

0.00

AC:

AN:

30050

South Asian (SAS)

AF:

0.00

AC:

AN:

53668

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4013

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

839893

Other (OTH)

AF:

0.00

AC:

AN:

45760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

111056

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33524

African (AFR)

AF:

0.00

AC:

AN:

30429

American (AMR)

AF:

0.00

AC:

AN:

10599

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2633

East Asian (EAS)

AF:

0.00

AC:

AN:

3495

South Asian (SAS)

AF:

0.00

AC:

AN:

2689

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6013

Middle Eastern (MID)

AF:

0.00

AC:

AN:

230

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52817

Other (OTH)

AF:

0.00

AC:

AN:

1486

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Kabuki syndrome 2 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.4

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over