6-26158234-C-A

Variant names:

• chr6-26158234-C-A
• NM_021063.4:c.65C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021063.4(H2BC5):​c.65C>A​(p.Ala22Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: H2BC5 NM_021063.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20

Genes affected

H2BC5 (HGNC:4747): (H2B clustered histone 5) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H2B family. Two transcripts that encode the same protein have been identified for this gene, which is found in the large histone gene cluster on chromosome 6p22-p21.3. [provided by RefSeq, Aug 2015]

ENSG00000291336 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24221319).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H2BC5	NM_021063.4	c.65C>A	p.Ala22Asp	missense_variant	Exon 1 of 1	ENST00000377777.6	NP_066407.1
H2BC5	NM_138720.2	c.65C>A	p.Ala22Asp	missense_variant	Exon 1 of 2		NP_619790.1
H2BC5	XM_005249039.5	c.65C>A	p.Ala22Asp	missense_variant	Exon 1 of 2		XP_005249096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H2BC5	ENST00000377777.6	c.65C>A	p.Ala22Asp	missense_variant	Exon 1 of 1	6	NM_021063.4	ENSP00000367008.4
H2BC5	ENST00000289316.2	c.65C>A	p.Ala22Asp	missense_variant	Exon 1 of 2	1		ENSP00000289316.2
ENSG00000291336	ENST00000707189.1	n.999+34063C>A		intron_variant	Intron 1 of 1
ENSG00000291338	ENST00000707191.1	n.1000+113C>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65C>A (p.A22D) alteration is located in exon 1 (coding exon 1) of the HIST1H2BD gene. This alteration results from a C to A substitution at nucleotide position 65, causing the alanine (A) at amino acid position 22 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	0.10
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.36	.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Benign	0.064
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.093	T;T
Polyphen		0.41	B;B
Vest4		0.33
MutPred		0.18		Loss of methylation at K25 (P = 0.2165);Loss of methylation at K25 (P = 0.2165);
MVP		0.43
MPC		1.6
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.72
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-26158462;