6-26183815-C-A

Position:

• chr6-26183815-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_003523.3(H2BC6):​c.20C>A​(p.Ser7Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000211 in 1,607,094 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S7C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: H2BC6 NM_003523.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

Genes affected

H2BC6 (HGNC:4753): (H2B clustered histone 6) 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. 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 large histone gene cluster on chromosome 6. [provided by RefSeq, Aug 2015]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a modified_residue ADP-ribosylserine (size 0) in uniprot entity H2B1C_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0126262605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H2BC6	NM_003523.3	c.20C>A	p.Ser7Tyr	missense_variant	1/1	ENST00000614097.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H2BC6	ENST00000614097.3	c.20C>A	p.Ser7Tyr	missense_variant	1/1		NM_003523.3	P1
	ENST00000707189.1	n.999+59644C>A		intron_variant, non_coding_transcript_variant
	ENST00000707191.1	n.1000+25694C>A		intron_variant, non_coding_transcript_variant
H2BC6	ENST00000634910.1	c.20C>A	p.Ser7Tyr	missense_variant	4/4	5		P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151766 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000426 AC: 107 AN: 251446 Hom.: 0 AF XY: 0.000383 AC XY: 52 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000208 AC: 303 AN: 1455328 Hom.: 1 Cov.: 30 AF XY: 0.000213 AC XY: 154 AN XY: 724034

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00494

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000114

Gnomad4 OTH exome AF: 0.000382

GnomAD4 genome AF: 0.000237 AC: 36 AN: 151766 Hom.: 0 Cov.: 32 AF XY: 0.000297 AC XY: 22 AN XY: 74174

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.000253

ExAC AF: 0.000339 AC: 41

EpiCase AF: 0.000600

EpiControl AF: 0.000474

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

Sep 01, 2021

The c.20C>A (p.S7Y) alteration is located in exon 1 (coding exon 1) of the HIST1H2BE gene. This alteration results from a C to A substitution at nucleotide position 20, causing the serine (S) at amino acid position 7 to be replaced by a tyrosine (Y). 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	Benign	-0.21	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Benign	0.97
Eigen	Benign	0.12
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.62	D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.95	D
PrimateAI	Pathogenic	0.84	D
Sift4G	Uncertain	0.0060	D;D
Vest4		0.51
MVP		0.30
ClinPred		0.11	T
GERP RS		5.1
gMVP		0.016

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs146757427; hg19: chr6-26184043;