6-27132459-C-T

Variant names:

• chr6-27132459-C-T
• NM_021058.4:c.292G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021058.4(H2BC11):​c.292G>A​(p.Ala98Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: H2BC11 NM_021058.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.39

Genes affected

H2BC11 (HGNC:4761): (H2B clustered histone 11) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H2B family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the histone microcluster on chromosome 6p21.33. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H2BC11	NM_021058.4	c.292G>A	p.Ala98Thr	missense_variant	Exon 1 of 1	ENST00000339812.3	NP_066402.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H2BC11	ENST00000339812.3	c.292G>A	p.Ala98Thr	missense_variant	Exon 1 of 1	6	NM_021058.4	ENSP00000342886.3
H2BC11	ENST00000607124.1	c.292G>A	p.Ala98Thr	missense_variant	Exon 1 of 2	3		ENSP00000476136.1
H2BC11	ENST00000606923.1	c.22+66G>A		intron_variant	Intron 1 of 1	3		ENSP00000475213.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.292G>A (p.A98T) alteration is located in exon 1 (coding exon 1) of the HIST1H2BJ gene. This alteration results from a G to A substitution at nucleotide position 292, causing the alanine (A) at amino acid position 98 to be replaced by a threonine (T). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.8	H;H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.6	.;D
REVEL	Benign	0.28
Sift	Benign	0.037	.;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.95	P;P
Vest4		0.91
MutPred		0.71		Gain of glycosylation at A98 (P = 0.0342);Gain of glycosylation at A98 (P = 0.0342);
MVP		0.75
MPC		0.50
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.45

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: chr6-27100238;