Genetic Variant NM_021062.3:c.14C>T (chr6-26043644-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_021062.3(H2BC3):c.14C>T(p.Ser5Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000394 in 1,602,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

H2BC3
NM_021062.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.94

Publications

1 publications found

Variant links:

Genes affected

H2BC3 (HGNC:4751): (H2B clustered histone 3) 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. Transcripts from this gene lack polyA tails; instead, they contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6p22-p21.3. [provided by RefSeq, Aug 2015]

H2BC3 links:

ENSG00000299111 (HGNC:):

ENSG00000299111 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12998596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H2BC3	NM_021062.3 link	c.14C>T	p.Ser5Phe	missense_variant	Exon 1 of 1	ENST00000615966.2	NP_066406.1	P33778

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H2BC3	ENST00000615966.2 link	c.14C>T	p.Ser5Phe	missense_variant	Exon 1 of 1	6	NM_021062.3	ENSP00000482674.2		P33778

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000271

AC:

AN:

240182

AF XY:

0.000308

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.000113

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000482

Gnomad NFE exome

AF:

0.000386

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.000411

AC:

596

AN:

1450288

Hom.:

Cov.:

AF XY:

0.000410

AC XY:

296

AN XY:

721132

show subpopulations

African (AFR)

AF:

0.0000912

AC:

AN:

32888

American (AMR)

AF:

0.000631

AC:

AN:

42800

Ashkenazi Jewish (ASJ)

AF:

0.000200

AC:

AN:

25052

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.00

AC:

AN:

84824

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52846

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.000483

AC:

534

AN:

1106726

Other (OTH)

AF:

0.000435

AC:

AN:

59818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000236

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0000721

AC:

AN:

41586

American (AMR)

AF:

0.000261

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000314

Hom.:

Bravo

AF:

0.000298

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.14C>T (p.S5F) alteration is located in exon 1 (coding exon 1) of the HIST1H2BB gene. This alteration results from a C to T substitution at nucleotide position 14, causing the serine (S) at amino acid position 5 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

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.040

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.0039

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

2.9

PrimateAI

Uncertain

0.62

Sift4G

Uncertain

0.0030

Polyphen

0.026

Vest4

0.36

MVP

0.28

ClinPred

0.063

GERP RS

4.4

PromoterAI

0.018

Neutral

(source)

Varity_R

0.067

gMVP

0.14

Mutation Taster

=96/4

polymorphism

(source)

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

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NM_021062.3:c.14C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over