6-113943382-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001527.4(HDAC2):c.1347A>C(p.Glu449Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000092 in 1,609,464 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000089 (2 hom.)
• Consequence: HDAC2 NM_001527.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0320

Genes affected

HDAC2 (HGNC:4853): (histone deacetylase 2) This gene product belongs to the histone deacetylase family. Histone deacetylases act via the formation of large multiprotein complexes, and are responsible for the deacetylation of lysine residues at the N-terminal regions of core histones (H2A, H2B, H3 and H4). This protein forms transcriptional repressor complexes by associating with many different proteins, including YY1, a mammalian zinc-finger transcription factor. Thus, it plays an important role in transcriptional regulation, cell cycle progression and developmental events. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13236722).
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC2	NM_001527.4	c.1347A>C	p.Glu449Asp	missense_variant	12/14	ENST00000519065.6
HDAC2	XM_047418692.1	c.1257A>C	p.Glu419Asp	missense_variant	12/14
HDAC2	NR_033441.2	n.1615A>C		non_coding_transcript_exon_variant	13/15
HDAC2	NR_073443.2	n.1545A>C		non_coding_transcript_exon_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC2	ENST00000519065.6	c.1347A>C	p.Glu449Asp	missense_variant	12/14	1	NM_001527.4	P1
HDAC2	ENST00000368632.6	c.1257A>C	p.Glu419Asp	missense_variant	13/15	2
HDAC2	ENST00000519108.5	c.1257A>C	p.Glu419Asp	missense_variant	12/14	2
HDAC2	ENST00000523334.1	n.4350A>C		non_coding_transcript_exon_variant	6/8	2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152188 Hom.: 0 Cov.: 33

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: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000135 AC: 33 AN: 245032 Hom.: 1 AF XY: 0.000150 AC XY: 20 AN XY: 133100

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000240

Gnomad NFE exome AF: 0.000250

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000885 AC: 129 AN: 1457276 Hom.: 2 Cov.: 30 AF XY: 0.0000924 AC XY: 67 AN XY: 724972

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000268

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.000149 AC: 18

EpiCase AF: 0.0000549

EpiControl AF: 0.000179

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.1347A>C (p.E449D) alteration is located in exon 12 (coding exon 12) of the HDAC2 gene. This alteration results from a A to C substitution at nucleotide position 1347, causing the glutamic acid (E) at amino acid position 449 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;.
Eigen	Benign	0.013
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.40	N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.040	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.37	T;T;T
Sift4G	Benign	0.56	T;T;T
Polyphen		0.96	P;.;.
Vest4		0.22
MutPred		0.14		Loss of helix (P = 0.028);.;.;
MVP		0.88
MPC		0.37
ClinPred		0.15	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.068
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs373953184; hg19: chr6-114264546;