6-113941730-C-T

Variant names:

• chr6-113941730-C-T
• rs1285296158
• NM_001527.4:c.1414G>A

Variant summary

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

The NM_001527.4(HDAC2):​c.1414G>A​(p.Gly472Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,296,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: HDAC2 NM_001527.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14014068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC2	NM_001527.4	c.1414G>A	p.Gly472Ser	missense_variant	Exon 13 of 14	ENST00000519065.6	NP_001518.3
HDAC2	XM_047418692.1	c.1324G>A	p.Gly442Ser	missense_variant	Exon 13 of 14		XP_047274648.1
HDAC2	NR_033441.2	n.1682G>A		non_coding_transcript_exon_variant	Exon 14 of 15
HDAC2	NR_073443.2	n.1612G>A		non_coding_transcript_exon_variant	Exon 13 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC2	ENST00000519065.6	c.1414G>A	p.Gly472Ser	missense_variant	Exon 13 of 14	1	NM_001527.4	ENSP00000430432.1
HDAC2	ENST00000368632.6	c.1324G>A	p.Gly442Ser	missense_variant	Exon 14 of 15	2		ENSP00000357621.2
HDAC2	ENST00000519108.5	c.1324G>A	p.Gly442Ser	missense_variant	Exon 13 of 14	2		ENSP00000430008.1
HDAC2	ENST00000523334.1	n.4417G>A		non_coding_transcript_exon_variant	Exon 7 of 8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1296652 Hom.: 0 Cov.: 18 AF XY: 0.00000154 AC XY: 1 AN XY: 649944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000372

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1414G>A (p.G472S) alteration is located in exon 13 (coding exon 13) of the HDAC2 gene. This alteration results from a G to A substitution at nucleotide position 1414, causing the glycine (G) at amino acid position 472 to be replaced by a serine (S). 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	0.062
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T;.;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.34	N;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.23
MutPred		0.21		Gain of phosphorylation at G472 (P = 9e-04);.;.;
MVP		0.65
MPC		0.40
ClinPred		0.22	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.16

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: rs1285296158; hg19: chr6-114262894;