chr2-239084260-C-T

Variant names:

Variant summary

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

The NM_001378414.1(HDAC4):c.2445-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000861 in 1,591,054 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 5 hom. )

Consequence

HDAC4
NM_001378414.1 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.69

Publications

0 publications found

Variant links:

Genes affected

HDAC4 (HGNC:14063): (histone deacetylase 4) 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 possesses histone deacetylase activity and represses transcription when tethered to a promoter. This protein does not bind DNA directly, but through transcription factors MEF2C and MEF2D. It seems to interact in a multiprotein complex with RbAp48 and HDAC3. [provided by RefSeq, Jul 2008]

HDAC4 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with central hypotonia and dysmorphic facies
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
2q37 microdeletion syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

HDAC4 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 (BayesDel_noAF=-0.96).

BP6

Variant 2-239084260-C-T is Benign according to our data. Variant chr2-239084260-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445454.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 = 0.00342 (520/152266) while in subpopulation AFR AF = 0.0104 (431/41540). AF 95% confidence interval is 0.00957. There are 3 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 520 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC4	NM_001378414.1 link	c.2445-18G>A		intron_variant	Intron 19 of 26	ENST00000543185.6	NP_001365343.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HDAC4	ENST00000543185.6 link	c.2445-18G>A	intron_variant	Intron 19 of 26	5	NM_001378414.1	ENSP00000440481.3	A0A7I2SVS4
HDAC4	ENST00000345617.7 link	c.2430-18G>A	intron_variant	Intron 19 of 26	1		ENSP00000264606.3	P56524-1
HDAC4	ENST00000487617.5 link	n.337-18G>A	intron_variant	Intron 5 of 7	3
HDAC4	ENST00000690129.1 link	n.459-18G>A	intron_variant	Intron 2 of 9

Frequencies

GnomAD3 genomes

AF:

0.00339

AC:

516

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0103

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00130

AC:

300

AN:

230160

AF XY:

0.00122

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.000367

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000597

Gnomad FIN exome

AF:

0.00487

Gnomad NFE exome

AF:

0.000312

Gnomad OTH exome

AF:

0.000693

GnomAD4 exome

AF:

0.000591

AC:

850

AN:

1438788

Hom.:

Cov.:

AF XY:

0.000566

AC XY:

405

AN XY:

715910

show subpopulations

African (AFR)

AF:

0.00986

AC:

324

AN:

32862

American (AMR)

AF:

0.000391

AC:

AN:

43466

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25900

East Asian (EAS)

AF:

0.0000513

AC:

AN:

38962

South Asian (SAS)

AF:

0.000189

AC:

AN:

84734

European-Finnish (FIN)

AF:

0.00412

AC:

216

AN:

52374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.000212

AC:

232

AN:

1095232

Other (OTH)

AF:

0.000722

AC:

AN:

59532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

110

146

183

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:

0.00342

AC:

520

AN:

152266

Hom.:

Cov.:

AF XY:

0.00326

AC XY:

243

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0104

AC:

431

AN:

41540

American (AMR)

AF:

0.00105

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00471

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68016

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

104

130

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:

0.00140

Hom.:

Bravo

AF:

0.00354

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.10

(source)

DANN

Benign

0.70

PhyloP100

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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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