rs2290089

Variant names:

• chr2-239164099-A-C
• rs2290089
• NM_001378414.1:c.491-176T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-239164099-A-C
• chr2-239164099-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001378414.1(HDAC4):​c.491-176T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 151,940 control chromosomes in the GnomAD database, including 29,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.62 (29608 hom., cov: 31)
• Consequence: HDAC4 NM_001378414.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00600
• Publications: 6 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 2q37 microdeletion syndrome

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-239164099-A-C is Benign according to our data. Variant chr2-239164099-A-C is described in ClinVar as Benign. ClinVar VariationId is 1246960.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.726 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC4	NM_001378414.1	MANE Select	c.491-176T>G		intron	N/A	NP_001365343.1	A0A7I2SVS4
	HDAC4	NM_001378415.1		c.491-176T>G		intron	N/A	NP_001365344.1	A0A7I2SVS4
	HDAC4	NM_001378416.1		c.491-176T>G		intron	N/A	NP_001365345.1	P56524-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC4	ENST00000543185.6	TSL:5 MANE Select	c.491-176T>G		intron	N/A	ENSP00000440481.3	A0A7I2SVS4
	HDAC4	ENST00000345617.7	TSL:1	c.491-176T>G		intron	N/A	ENSP00000264606.3	P56524-1
	HDAC4	ENST00000463007.5	TSL:1	n.943-176T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93644 AN: 151820 Hom.: 29596 Cov.: 31

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.745

Gnomad FIN AF: 0.740

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.593

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

GnomAD4 genome AF: 0.617 AC: 93686 AN: 151940 Hom.: 29608 Cov.: 31 AF XY: 0.618 AC XY: 45863 AN XY: 74248

African (AFR) AF: 0.541 AC: 22410 AN: 41426

American (AMR) AF: 0.469 AC: 7152 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2263 AN: 3468

East Asian (EAS) AF: 0.460 AC: 2365 AN: 5144

South Asian (SAS) AF: 0.746 AC: 3602 AN: 4828

European-Finnish (FIN) AF: 0.740 AC: 7797 AN: 10542

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.677 AC: 46012 AN: 67956

Other (OTH) AF: 0.596 AC: 1258 AN: 2110

Alfa AF: 0.654 Hom.: 51024

Bravo AF: 0.589

Asia WGS AF: 0.614 AC: 2137 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.56
PhyloP100		-0.0060
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2290089;

hg19: chr2-240085795;