6-26240671-C-T

Variant names:

• chr6-26240671-C-T
• rs115414626
• NM_003540.4:c.246C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_003540.4(H4C6):​c.246C>T​(p.Val82Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,612,128 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (3 hom.)
• Consequence: H4C6 NM_003540.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.267
• Publications: 1 publications found

Genes affected

H4C6 (HGNC:4783): (H4 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 H4 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]

ENSG00000291336 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 6-26240671-C-T is Benign according to our data. Variant chr6-26240671-C-T is described in ClinVar as Benign. ClinVar VariationId is 719489.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.267 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003540.4. 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
	H4C6	NM_003540.4	MANE Select	c.246C>T	p.Val82Val	synonymous	Exon 1 of 1	NP_003531.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H4C6	ENST00000244537.6	TSL:6 MANE Select	c.246C>T	p.Val82Val	synonymous	Exon 1 of 1	ENSP00000244537.6	P62805
	ENSG00000291336	ENST00000707189.1		n.999+116500C>T		intron	N/A
	ENSG00000291338	ENST00000707191.1		n.1000+82550C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 272 AN: 152242 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000426 AC: 106 AN: 248660 AF XY: 0.000320

Gnomad AFR exome AF: 0.00493

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000447

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000177 AC: 258 AN: 1459770 Hom.: 3 Cov.: 32 AF XY: 0.000147 AC XY: 107 AN XY: 726114

African (AFR) AF: 0.00502 AC: 168 AN: 33468

American (AMR) AF: 0.000493 AC: 22 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.0000931 AC: 8 AN: 85964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1110686

Other (OTH) AF: 0.000514 AC: 31 AN: 60306

GnomAD4 genome AF: 0.00180 AC: 275 AN: 152358 Hom.: 1 Cov.: 33 AF XY: 0.00177 AC XY: 132 AN XY: 74494

African (AFR) AF: 0.00608 AC: 253 AN: 41586

American (AMR) AF: 0.00118 AC: 18 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000888 Hom.: 0

Bravo AF: 0.00196

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.6
DANN	Benign	0.87
PhyloP100		0.27
PromoterAI		0.010	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs115414626; hg19: chr6-26240899;