6-113956005-T-G

Position:

• chr6-113956005-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001527.4(HDAC2):​c.497+8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: HDAC2 NM_001527.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005305
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.88

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23028594).
• BP6: Variant 6-113956005-T-G is Benign according to our data. Variant chr6-113956005-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3045365.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC2	NM_001527.4	c.497+8A>C		splice_region_variant, intron_variant		ENST00000519065.6	NP_001518.3
HDAC2	XM_047418692.1	c.407+8A>C		splice_region_variant, intron_variant			XP_047274648.1
HDAC2	NR_033441.2	n.765+8A>C		splice_region_variant, intron_variant, non_coding_transcript_variant
HDAC2	NR_073443.2	n.695+8A>C		splice_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC2	ENST00000519065.6	c.497+8A>C		splice_region_variant, intron_variant		1	NM_001527.4	ENSP00000430432	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430004 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 711816

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: 9.14e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HDAC2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.2
DANN	Uncertain	0.99
Eigen	Benign	0.11
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.96	N;N;N;N
PROVEAN	Benign	0.090	N
REVEL	Benign	0.042
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.041	D
MutPred		0.61		Gain of methylation at K156 (P = 0.0954);
MVP		0.37
ClinPred		0.060	T
GERP RS		-0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00053
dbscSNV1_RF	Benign	0.12
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: rs1312623763; hg19: chr6-114277169;