Genetic Variant HDAC6:p.Gln18Lys (chrX-48802744-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006044.4(HDAC6):c.52C>A(p.Gln18Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,095,357 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q18E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

HDAC6
NM_006044.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.983

Publications

0 publications found

Variant links:

Genes affected

HDAC6 (HGNC:14064): (histone deacetylase 6) Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It contains an internal duplication of two catalytic domains which appear to function independently of each other. This protein possesses histone deacetylase activity and represses transcription. [provided by RefSeq, Jul 2008]

HDAC6 Gene-Disease associations (from GenCC):

X-linked dominant chondrodysplasia, Chassaing-Lacombe type
Inheritance: XL Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

HDAC6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06308165).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006044.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HDAC6	NM_006044.4	MANE Select	c.52C>A	p.Gln18Lys	missense	Exon 2 of 29	NP_006035.2
HDAC6	NM_001321225.2		c.94C>A	p.Gln32Lys	missense	Exon 3 of 30	NP_001308154.1	B4DZH6
HDAC6	NM_001321226.2		c.52C>A	p.Gln18Lys	missense	Exon 2 of 29	NP_001308155.1	Q9UBN7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HDAC6	ENST00000334136.11	TSL:1 MANE Select	c.52C>A	p.Gln18Lys	missense	Exon 2 of 29	ENSP00000334061.5	Q9UBN7-1
HDAC6	ENST00000376619.7	TSL:1	c.52C>A	p.Gln18Lys	missense	Exon 2 of 29	ENSP00000365804.2	Q9UBN7-1
HDAC6	ENST00000462730.5	TSL:1	c.52C>A	p.Gln18Lys	missense	Exon 2 of 6	ENSP00000496727.1	Q9BRX7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000114

AC:

AN:

175553

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:

0.000149

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1095357

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360943

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26329

American (AMR)

AF:

0.00

AC:

AN:

34993

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19334

East Asian (EAS)

AF:

0.0000665

AC:

AN:

30086

South Asian (SAS)

AF:

0.00

AC:

AN:

53583

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40325

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840583

Other (OTH)

AF:

0.00

AC:

AN:

45989

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

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.29

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.83

M_CAP

Benign

0.018

MetaRNN

Benign

0.063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.98

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.61

REVEL

Benign

0.061

Sift

Benign

0.72

Sift4G

Benign

0.19

Polyphen

0.015

Vest4

0.14

MutPred

0.13

Gain of methylation at Q18 (P = 0.0019)

MVP

0.46

MPC

1.1

ClinPred

0.0083

GERP RS

3.2

PromoterAI

0.023

Neutral

(source)

Varity_R

0.10

gMVP

0.16

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over