6-26123711-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003526.3(H2BC4):c.194C>T(p.Ser65Phe) variant causes a missense change involving the alteration of a conserved nucleotide. 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: H2BC4 NM_003526.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

Genes affected

H2BC4 (HGNC:4757): (H2B clustered histone 4) 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. The protein has antibacterial and antifungal antimicrobial activity. The main transcript variant of this gene is intronless and encodes a replication-dependent histone that is a member of the histone H2B family. This transcript variant lacks a polyA tail but instead contains a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6. [provided by RefSeq, Apr 2020]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H2BC4	NM_003526.3	c.194C>T	p.Ser65Phe	missense_variant	1/1	ENST00000396984.2
H2BC4	NM_001381989.1	c.194C>T	p.Ser65Phe	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H2BC4	ENST00000396984.2	c.194C>T	p.Ser65Phe	missense_variant	1/1		NM_003526.3	P1
H2BC4	ENST00000314332.5	c.194C>T	p.Ser65Phe	missense_variant	1/2	1		P1
	ENST00000707189.1	n.539G>A		non_coding_transcript_exon_variant	1/2
H2BC4	ENST00000707188.1	c.194C>T	p.Ser65Phe	missense_variant, NMD_transcript_variant	1/3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The c.194C>T (p.S65F) alteration is located in exon 1 (coding exon 1) of the HIST1H2BC gene. This alteration results from a C to T substitution at nucleotide position 194, causing the serine (S) at amino acid position 65 to be replaced by a phenylalanine (F). 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
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.42	T;T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.080	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.86		Loss of disorder (P = 0.1289);Loss of disorder (P = 0.1289);
MVP		0.78
MPC		1.6
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.28

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: chr6-26123939; COSMIC: COSV58417027; COSMIC: COSV58417027;