6-113970880-T-C

Position:

• chr6-113970880-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001527.4(HDAC2):​c.29A>G​(p.Lys10Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: HDAC2 NM_001527.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38

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]

HDAC2-AS2 (HGNC:43590): (HDAC2 and HS3ST5 antisense RNA 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18638235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC2	NM_001527.4	c.29A>G	p.Lys10Arg	missense_variant	1/14	ENST00000519065.6	NP_001518.3
HDAC2-AS2	NR_125845.1	n.578+602T>C		intron_variant, non_coding_transcript_variant
HDAC2	NR_033441.2	n.269A>G		non_coding_transcript_exon_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC2	ENST00000519065.6	c.29A>G	p.Lys10Arg	missense_variant	1/14	1	NM_001527.4	ENSP00000430432	P1
HDAC2-AS2	ENST00000519104.5	n.578+602T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

May 14, 2024

The c.29A>G (p.K10R) alteration is located in exon 1 (coding exon 1) of the HDAC2 gene. This alteration results from a A to G substitution at nucleotide position 29, causing the lysine (K) at amino acid position 10 to be replaced by an arginine (R). 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	0.068
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-0.086
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.62	N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.19
Sift	Benign	0.68	T;T
Sift4G	Benign	0.75	T;.
Vest4		0.35
MutPred		0.43		Loss of methylation at K10 (P = 0.0151);Loss of methylation at K10 (P = 0.0151);
MVP		0.74
MPC		1.4
ClinPred		0.32	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.84

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: rs1771213289; hg19: chr6-114292044;