6-113953359-T-G

Variant names:

• chr6-113953359-T-G
• NM_001527.4:c.557A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001527.4(HDAC2):​c.557A>C​(p.Glu186Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HDAC2 NM_001527.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 8.02

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC2	NM_001527.4	c.557A>C	p.Glu186Ala	missense_variant	Exon 6 of 14	ENST00000519065.6	NP_001518.3
HDAC2	XM_047418692.1	c.467A>C	p.Glu156Ala	missense_variant	Exon 6 of 14		XP_047274648.1
HDAC2	NR_033441.2	n.825A>C		non_coding_transcript_exon_variant	Exon 7 of 15
HDAC2	NR_073443.2	n.755A>C		non_coding_transcript_exon_variant	Exon 6 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC2	ENST00000519065.6	c.557A>C	p.Glu186Ala	missense_variant	Exon 6 of 14	1	NM_001527.4	ENSP00000430432.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

HDAC2-related disorder Uncertain:1

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HDAC2 c.557A>C variant is predicted to result in the amino acid substitution p.Glu186Ala. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.061	D
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.97	D;.;.
Vest4		0.69
MutPred		0.72		Loss of disorder (P = 0.034);.;.;
MVP		0.81
MPC		3.0
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.93
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-114274523;