6-113956654-A-G

Position:

• chr6-113956654-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001527.4(HDAC2):​c.323T>C​(p.Phe108Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HDAC2 NM_001527.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.07

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC2	NM_001527.4	c.323T>C	p.Phe108Ser	missense_variant	4/14	ENST00000519065.6	NP_001518.3
HDAC2	XM_047418692.1	c.233T>C	p.Phe78Ser	missense_variant	4/14		XP_047274648.1
HDAC2	NR_033441.2	n.591T>C		non_coding_transcript_exon_variant	5/15
HDAC2	NR_073443.2	n.521T>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.323T>C	p.Phe108Ser	missense_variant	4/14	1	NM_001527.4	ENSP00000430432	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461042 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726854

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

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

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 11, 2020

Variant summary: HDAC2 c.323T>C (p.Phe108Ser) results in a non-conservative amino acid change located in the Histone deacetylase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249212 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.323T>C in individuals affected with HDAC2-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;.;.;T;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;.;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.2	D;D;D;D;D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D;D;D;D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;T;.;.;T
Polyphen		0.54	P;.;.;.;.;.;.
Vest4		0.88
MutPred		0.78		Gain of disorder (P = 0.0719);.;.;.;.;.;.;
MVP		0.96
MPC		3.4
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.98

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: rs1776561501; hg19: chr6-114277818;