6-113956005-T-G

Variant names:

• chr6-113956005-T-G
• rs1312623763
• NM_001527.4:c.497+8A>C

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 3045365.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001527.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC2	NM_001527.4	MANE Select	c.497+8A>C		splice_region intron	N/A	NP_001518.3	Q92769-1
	HDAC2	NR_033441.2		n.765+8A>C		splice_region intron	N/A
	HDAC2	NR_073443.2		n.695+8A>C		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC2	ENST00000519065.6	TSL:1 MANE Select	c.497+8A>C		splice_region intron	N/A	ENSP00000430432.1	Q92769-1
	HDAC2	ENST00000425835.6	TSL:2	c.475A>C	p.Asn159His	missense	Exon 5 of 5	ENSP00000417026.2	H3BM24
	HDAC2	ENST00000916847.1		c.497+8A>C		splice_region intron	N/A	ENSP00000586906.1

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

African (AFR) AF: 0.00 AC: 0 AN: 32058

American (AMR) AF: 0.00 AC: 0 AN: 39866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39170

South Asian (SAS) AF: 0.00 AC: 0 AN: 82000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1094424

Other (OTH) AF: 0.00 AC: 0 AN: 59154

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HDAC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
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
PhyloP100		-1.9
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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1312623763; hg19: chr6-114277169;