rs200484

Positions:

• chr6-27807896-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003519.4(H2BC13):​c.11T>C​(p.Leu4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,613,976 control chromosomes in the GnomAD database, including 12,384 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1307 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11077 hom.)
• Consequence: H2BC13 NM_003519.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.48

Genes affected

H2BC13 (HGNC:4748): (H2B clustered histone 13) 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 small histone gene cluster on chromosome 6p22-p21.3. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015999079).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H2BC13	NM_003519.4	c.11T>C	p.Leu4Pro	missense_variant	1/1	ENST00000377401.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H2BC13	ENST00000377401.4	c.11T>C	p.Leu4Pro	missense_variant	1/1		NM_003519.4	P1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18631 AN: 152020 Hom.: 1306 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.0821

Gnomad SAS AF: 0.0764

Gnomad FIN AF: 0.0485

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0975

GnomAD3 exomes AF: 0.0983 AC: 24697 AN: 251350 Hom.: 1452 AF XY: 0.0951 AC XY: 12913 AN XY: 135848

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.0793

Gnomad SAS exome AF: 0.0769

Gnomad FIN exome AF: 0.0505

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.0863

GnomAD4 exome AF: 0.118 AC: 172086 AN: 1461838 Hom.: 11077 Cov.: 32 AF XY: 0.115 AC XY: 83460 AN XY: 727220

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.0370

Gnomad4 EAS exome AF: 0.0874

Gnomad4 SAS exome AF: 0.0759

Gnomad4 FIN exome AF: 0.0535

Gnomad4 NFE exome AF: 0.126

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.123 AC: 18643 AN: 152138 Hom.: 1307 Cov.: 32 AF XY: 0.118 AC XY: 8764 AN XY: 74414

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.0821

Gnomad4 SAS AF: 0.0771

Gnomad4 FIN AF: 0.0485

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.0965

Alfa AF: 0.105 Hom.: 1839

Bravo AF: 0.131

TwinsUK AF: 0.147 AC: 544

ALSPAC AF: 0.135 AC: 521

ESP6500AA AF: 0.189 AC: 831

ESP6500EA AF: 0.111 AC: 955

ExAC AF: 0.0990 AC: 12020

Asia WGS AF: 0.0810 AC: 283 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.1
DANN	Benign	0.51
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.97	N
MutationTaster	Benign	0.022	P
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	4.4	N
REVEL	Benign	0.093
Sift	Benign	1.0	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.052
MPC		0.67
ClinPred		0.020	T
GERP RS		4.3
Varity_R		0.086
gMVP		0.0093

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

LitVar

Other links and lift over

dbSNP: rs200484; hg19: chr6-27775674;