NM_001527.4:c.1318_1321delAAAG

Variant summary

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

The NM_001527.4(HDAC2):​c.1318_1321delAAAG​(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

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 7.43
Variant links:
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]

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ACMG classification

Classification made for transcript

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 rank MANE Protein UniProt
HDAC2NM_001527.4 linkc.1318_1321delAAAG p.Lys440GlufsTer65 frameshift_variant Exon 12 of 14 ENST00000519065.6 NP_001518.3 Q92769-1
HDAC2XM_047418692.1 linkc.1228_1231delAAAG p.Lys410GlufsTer65 frameshift_variant Exon 12 of 14 XP_047274648.1
HDAC2NR_033441.2 linkn.1586_1589delAAAG non_coding_transcript_exon_variant Exon 13 of 15
HDAC2NR_073443.2 linkn.1516_1519delAAAG non_coding_transcript_exon_variant Exon 12 of 14

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HDAC2ENST00000519065.6 linkc.1318_1321delAAAG p.Lys440GlufsTer65 frameshift_variant Exon 12 of 14 1 NM_001527.4 ENSP00000430432.1 Q92769-1
HDAC2ENST00000368632.6 linkc.1228_1231delAAAG p.Lys410GlufsTer65 frameshift_variant Exon 13 of 15 2 ENSP00000357621.2 Q92769-3
HDAC2ENST00000519108.5 linkc.1228_1231delAAAG p.Lys410GlufsTer65 frameshift_variant Exon 12 of 14 2 ENSP00000430008.1 Q92769-3
HDAC2ENST00000523334.1 linkn.4321_4324delAAAG non_coding_transcript_exon_variant Exon 6 of 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
LINK: link

Submissions by phenotype

HDAC2-related disorder Uncertain:1
May 25, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

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

Name
Calibrated prediction
Score
Prediction

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; API