6-113960025-T-C

Position:

• chr6-113960025-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001527.4(HDAC2):​c.53-7A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,299,008 control chromosomes in the GnomAD database, including 116 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (64 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (52 hom.)
• Consequence: HDAC2 NM_001527.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007922
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.789

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033639967).
• BP6: Variant 6-113960025-T-C is Benign according to our data. Variant chr6-113960025-T-C is described in ClinVar as [Benign]. Clinvar id is 778921.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC2	NM_001527.4	c.53-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000519065.6
HDAC2	XM_047418692.1	c.-38-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
HDAC2	NR_033441.2	n.321-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant
HDAC2	NR_073443.2	n.251-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC2	ENST00000519065.6	c.53-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001527.4	P1

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2384 AN: 151954 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.00399 AC: 983 AN: 246598 Hom.: 21 AF XY: 0.00301 AC XY: 404 AN XY: 134096

Gnomad AFR exome AF: 0.0574

Gnomad AMR exome AF: 0.00244

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000986

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00184 AC: 2112 AN: 1146936 Hom.: 52 Cov.: 16 AF XY: 0.00163 AC XY: 955 AN XY: 585968

Gnomad4 AFR exome AF: 0.0606

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000138

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000136

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.0157 AC: 2386 AN: 152072 Hom.: 64 Cov.: 32 AF XY: 0.0151 AC XY: 1121 AN XY: 74320

Gnomad4 AFR AF: 0.0548

Gnomad4 AMR AF: 0.00537

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00844 Hom.: 13

Bravo AF: 0.0182

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0535 AC: 198

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.00479 AC: 579

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.1
DANN	Benign	0.86
DEOGEN2	Benign	0.073	T
Eigen	Benign	0.10
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	0.020	N
REVEL	Benign	0.044
Sift	Benign	1.0	T
MVP		0.51
ClinPred		0.0075	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000079
dbscSNV1_RF	Benign	0.066
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: rs114260386; hg19: chr6-114281189;