chr6-113943407-CCTTT-C

Position:

• chr6-113943407-CCTTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001527.4(HDAC2):​c.1318_1321del​(p.Lys440GlufsTer65) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HDAC2 NM_001527.4 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.43

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC2	NM_001527.4	c.1318_1321del	p.Lys440GlufsTer65	frameshift_variant	12/14	ENST00000519065.6	NP_001518.3
HDAC2	XM_047418692.1	c.1228_1231del	p.Lys410GlufsTer65	frameshift_variant	12/14		XP_047274648.1
HDAC2	NR_033441.2	n.1586_1589del		non_coding_transcript_exon_variant	13/15
HDAC2	NR_073443.2	n.1516_1519del		non_coding_transcript_exon_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC2	ENST00000519065.6	c.1318_1321del	p.Lys440GlufsTer65	frameshift_variant	12/14	1	NM_001527.4	ENSP00000430432	P1
HDAC2	ENST00000368632.6	c.1228_1231del	p.Lys410GlufsTer65	frameshift_variant	13/15	2		ENSP00000357621
HDAC2	ENST00000519108.5	c.1228_1231del	p.Lys410GlufsTer65	frameshift_variant	12/14	2		ENSP00000430008
HDAC2	ENST00000523334.1	n.4321_4324del		non_coding_transcript_exon_variant	6/8	2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

HDAC2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 25, 2024

The HDAC2 c.1318_1321delAAAG variant is predicted to result in a frameshift and premature protein termination (p.Lys440Glufs*65). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Loss of function is not a conclusively established mechanism for HDAC2-related disease and only a few protein truncating variants have been reported to date (Kaplanis et al. 2020. PubMed ID: 33057194; Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). 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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-114264571;