6-113956687-A-G

Position:

• chr6-113956687-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001527.4(HDAC2):​c.290T>C​(p.Val97Ala) 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: 9.08

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC2	NM_001527.4	c.290T>C	p.Val97Ala	missense_variant	4/14	ENST00000519065.6	NP_001518.3
HDAC2	XM_047418692.1	c.200T>C	p.Val67Ala	missense_variant	4/14		XP_047274648.1
HDAC2	NR_033441.2	n.558T>C		non_coding_transcript_exon_variant	5/15
HDAC2	NR_073443.2	n.488T>C		non_coding_transcript_exon_variant	4/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC2	ENST00000519065.6	c.290T>C	p.Val97Ala	missense_variant	4/14	1	NM_001527.4	ENSP00000430432.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Genomics Laboratory, Stanford Medicine

Dec 30, 2019

The p.Val97Ala variant in the HDAC2 gene was identified de novo in this individual, but has not been previously reported in association with disease and was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Val97Ala variant is uncertain; however, there is suspicion that this variant could be associated with an emerging HDAC2-associated disease due to this variant being identified de novo in this individual, and a different amino acid change (p.Val97Gly) at this residue being reported de novo in an individual with dysmorphic features and brain anomalies (P. Campeau, personal communication 2019). Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PS2_supporting; PM2; PP3] -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.;.;T;D;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.057	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;.;.;D;.;D
Polyphen		1.0	D;.;.;.;.;.;.;.;.
Vest4		0.80
MutPred		0.57		Loss of stability (P = 0.0153);.;.;.;.;.;.;.;.;
MVP		0.87
MPC		2.4
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.95

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: rs1776561731; hg19: chr6-114277851;