X-48823187-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006044.4(HDAC6):c.2788G>C(p.Gly930Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000537 in 1,205,258 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 194 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., 48 hem., cov: 23)

Exomes 𝑓: 0.00044 ( 0 hom. 146 hem. )

Consequence

HDAC6
NM_006044.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.855

Publications

1 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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

HDAC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074141026).

BP6

Variant X-48823187-G-C is Benign according to our data. Variant chrX-48823187-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 446055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 48 XL gene

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
HDAC6	NM_006044.4	MANE Select	c.2788G>C	p.Gly930Arg	missense	Exon 25 of 29	NP_006035.2
HDAC6	NM_001321225.2		c.2830G>C	p.Gly944Arg	missense	Exon 26 of 30	NP_001308154.1
HDAC6	NM_001321226.2		c.2788G>C	p.Gly930Arg	missense	Exon 25 of 29	NP_001308155.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HDAC6	ENST00000334136.11	TSL:1 MANE Select	c.2788G>C	p.Gly930Arg	missense	Exon 25 of 29	ENSP00000334061.5
HDAC6	ENST00000376619.7	TSL:1	c.2788G>C	p.Gly930Arg	missense	Exon 25 of 29	ENSP00000365804.2
HDAC6	ENST00000477528.5	TSL:1	n.3602G>C		non_coding_transcript_exon	Exon 24 of 28

Frequencies

GnomAD3 genomes

AF:

0.00153

AC:

171

AN:

111573

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00570

Gnomad ASJ

AF:

0.00608

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000170

Gnomad OTH

AF:

0.00668

GnomAD2 exomes

AF:

0.000771

AC:

130

AN:

168672

AF XY:

0.000535

show subpopulations

Gnomad AFR exome

AF:

0.00276

Gnomad AMR exome

AF:

0.000725

Gnomad ASJ exome

AF:

0.00726

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000216

Gnomad OTH exome

AF:

0.00237

GnomAD4 exome

AF:

0.000435

AC:

476

AN:

1093633

Hom.:

Cov.:

AF XY:

0.000406

AC XY:

146

AN XY:

359623

show subpopulations

African (AFR)

AF:

0.00323

AC:

AN:

26331

American (AMR)

AF:

0.00101

AC:

AN:

34648

Ashkenazi Jewish (ASJ)

AF:

0.00882

AC:

170

AN:

19266

East Asian (EAS)

AF:

0.00

AC:

AN:

30066

South Asian (SAS)

AF:

0.00

AC:

AN:

53238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40201

Middle Eastern (MID)

AF:

0.00194

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.000129

AC:

108

AN:

839864

Other (OTH)

AF:

0.00153

AC:

AN:

45893

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00153

AC:

171

AN:

111625

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

AN XY:

33831

show subpopulations

African (AFR)

AF:

0.00247

AC:

AN:

30730

American (AMR)

AF:

0.00569

AC:

AN:

10542

Ashkenazi Jewish (ASJ)

AF:

0.00608

AC:

AN:

2631

East Asian (EAS)

AF:

0.00

AC:

AN:

3534

South Asian (SAS)

AF:

0.00

AC:

AN:

2613

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6155

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000170

AC:

AN:

53002

Other (OTH)

AF:

0.00659

AC:

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

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:

0.000916

Hom.:

Bravo

AF:

0.00251

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00313

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.000825

AC:

100

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.31

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0074

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.75

PhyloP100

0.85

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.4

REVEL

Benign

0.095

Sift

Benign

0.17

Sift4G

Uncertain

0.039

Polyphen

0.24

Vest4

0.25

MutPred

0.36

Gain of methylation at G930 (P = 0.0374)

MVP

0.53

MPC

0.23

ClinPred

0.0092

GERP RS

3.1

PromoterAI

-0.0079

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.071

gMVP

0.39

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over