2-239198786-C-G

Variant names:

• chr2-239198786-C-G
• rs507159
• NM_001378414.1:c.95-8709G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378414.1(HDAC4):​c.95-8709G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 152,020 control chromosomes in the GnomAD database, including 25,464 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (25464 hom., cov: 32)
• Consequence: HDAC4 NM_001378414.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 2 publications found

Genes affected

HDAC4 (HGNC:14063): (histone deacetylase 4) Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. This protein does not bind DNA directly, but through transcription factors MEF2C and MEF2D. It seems to interact in a multiprotein complex with RbAp48 and HDAC3. [provided by RefSeq, Jul 2008]

HDAC4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with central hypotonia and dysmorphic facies

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 2q37 microdeletion syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378414.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC4	NM_001378414.1	MANE Select	c.95-8709G>C		intron	N/A	NP_001365343.1
	HDAC4	NM_001378415.1		c.95-8709G>C		intron	N/A	NP_001365344.1
	HDAC4	NM_001378416.1		c.95-8709G>C		intron	N/A	NP_001365345.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC4	ENST00000543185.6	TSL:5 MANE Select	c.95-8709G>C		intron	N/A	ENSP00000440481.3
	HDAC4	ENST00000345617.7	TSL:1	c.95-8709G>C		intron	N/A	ENSP00000264606.3
	HDAC4	ENST00000463007.5	TSL:1	n.547-8709G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84693 AN: 151902 Hom.: 25467 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.663

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.763

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.660

Gnomad OTH AF: 0.567

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.557 AC: 84708 AN: 152020 Hom.: 25464 Cov.: 32 AF XY: 0.562 AC XY: 41784 AN XY: 74330

African (AFR) AF: 0.322 AC: 13345 AN: 41436

American (AMR) AF: 0.600 AC: 9157 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2166 AN: 3472

East Asian (EAS) AF: 0.393 AC: 2025 AN: 5150

South Asian (SAS) AF: 0.638 AC: 3082 AN: 4828

European-Finnish (FIN) AF: 0.763 AC: 8083 AN: 10588

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.660 AC: 44881 AN: 67958

Other (OTH) AF: 0.563 AC: 1189 AN: 2112

Alfa AF: 0.507 Hom.: 1728

Bravo AF: 0.534

Asia WGS AF: 0.470 AC: 1637 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.0
DANN	Benign	0.61
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs507159; hg19: chr2-240120482;