6-26124015-G-T

Variant names:

• chr6-26124015-G-T
• rs198820
• ENST00000904682.1:c.-111C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000904682.1(H2BC4):​c.-111C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000231 in 1,300,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: H2BC4 ENST00000904682.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.90
• Publications: 0 publications found

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]

ENSG00000291336 (HGNC:):

H2AC6 (HGNC:4733): (H2A 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. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H2A 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]

H2AC6 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000904682.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H2AC6	NM_003512.4	MANE Select	c.-218G>T		upstream_gene	N/A	NP_003503.1	Q93077
	H2BC4	NM_003526.3	MANE Select	c.-111C>A		upstream_gene	N/A	NP_003517.2
	H2BC4	NM_001381989.1		c.-111C>A		upstream_gene	N/A	NP_001368918.1	P62807

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H2BC4	ENST00000904682.1		c.-111C>A		5_prime_UTR	Exon 1 of 2	ENSP00000574741.1
	ENSG00000291336	ENST00000707189.1		n.843G>T		non_coding_transcript_exon	Exon 1 of 2
	H2AC6	ENST00000377791.4	TSL:1 MANE Select	c.-218G>T		upstream_gene	N/A	ENSP00000367022.2	Q93077

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000231 AC: 3 AN: 1300558 Hom.: 0 Cov.: 21 AF XY: 0.00000310 AC XY: 2 AN XY: 644156

African (AFR) AF: 0.00 AC: 0 AN: 28858

American (AMR) AF: 0.00 AC: 0 AN: 28588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20102

East Asian (EAS) AF: 0.00 AC: 0 AN: 38766

South Asian (SAS) AF: 0.00 AC: 0 AN: 70612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5034

European-Non Finnish (NFE) AF: 0.00000199 AC: 2 AN: 1004398

Other (OTH) AF: 0.0000184 AC: 1 AN: 54242

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.3
DANN	Benign	0.62
PhyloP100		-1.9
PromoterAI		-0.073	Neutral

Splicing

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

Other links and lift over

dbSNP: rs198820; hg19: chr6-26124243;