5-87399457-A-G

Variant names:

• chr5-87399457-A-G
• rs2230641
• NM_001239.4:c.809T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001239.4(CCNH):​c.809T>C​(p.Val270Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,612,358 control chromosomes in the GnomAD database, including 32,656 homozygotes. 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: 𝑓 0.17 (2605 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30051 hom.)
• Consequence: CCNH NM_001239.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.47
• Publications: 70 publications found

Genes affected

CCNH (HGNC:1594): (cyclin H) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with CDK7 kinase and ring finger protein MAT1. The kinase complex is able to phosphorylate CDK2 and CDC2 kinases, thus functions as a CDK-activating kinase (CAK). This cyclin and its kinase partner are components of TFIIH, as well as RNA polymerase II protein complexes. They participate in two different transcriptional regulation processes, suggesting an important link between basal transcription control and the cell cycle machinery. A pseudogene of this gene is found on chromosome 4. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Nov 2010]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016247034).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCNH	NM_001239.4	c.809T>C	p.Val270Ala	missense_variant	Exon 7 of 9	ENST00000256897.9	NP_001230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCNH	ENST00000256897.9	c.809T>C	p.Val270Ala	missense_variant	Exon 7 of 9	1	NM_001239.4	ENSP00000256897.4

Frequencies

GnomAD3 genomes AF: 0.171 AC: 26026 AN: 152020 Hom.: 2603 Cov.: 32

Gnomad AFR AF: 0.0790

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.0879

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.206

GnomAD2 exomes AF: 0.180 AC: 45218 AN: 250990 AF XY: 0.184

Gnomad AFR exome AF: 0.0774

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.0883

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.222

Gnomad OTH exome AF: 0.212

GnomAD4 exome AF: 0.197 AC: 287881 AN: 1460220 Hom.: 30051 Cov.: 31 AF XY: 0.197 AC XY: 143216 AN XY: 726502

African (AFR) AF: 0.0788 AC: 2635 AN: 33458

American (AMR) AF: 0.111 AC: 4951 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 5857 AN: 26118

East Asian (EAS) AF: 0.0862 AC: 3421 AN: 39684

South Asian (SAS) AF: 0.142 AC: 12204 AN: 86220

European-Finnish (FIN) AF: 0.259 AC: 13832 AN: 53308

Middle Eastern (MID) AF: 0.215 AC: 1238 AN: 5768

European-Non Finnish (NFE) AF: 0.209 AC: 232059 AN: 1110610

Other (OTH) AF: 0.194 AC: 11684 AN: 60344

GnomAD4 genome AF: 0.171 AC: 26029 AN: 152138 Hom.: 2605 Cov.: 32 AF XY: 0.172 AC XY: 12795 AN XY: 74376

African (AFR) AF: 0.0787 AC: 3268 AN: 41518

American (AMR) AF: 0.164 AC: 2511 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 762 AN: 3472

East Asian (EAS) AF: 0.0875 AC: 454 AN: 5186

South Asian (SAS) AF: 0.134 AC: 648 AN: 4822

European-Finnish (FIN) AF: 0.261 AC: 2760 AN: 10566

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14939 AN: 67980

Other (OTH) AF: 0.207 AC: 438 AN: 2112

Alfa AF: 0.204 Hom.: 10493

Bravo AF: 0.159

TwinsUK AF: 0.208 AC: 770

ALSPAC AF: 0.213 AC: 821

ESP6500AA AF: 0.0801 AC: 353

ESP6500EA AF: 0.224 AC: 1925

ExAC AF: 0.182 AC: 22049

Asia WGS AF: 0.114 AC: 396 AN: 3478

EpiCase AF: 0.221

EpiControl AF: 0.225

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	.;M;.
PhyloP100		8.5
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.96	.;D;.
Vest4		0.19
MPC		0.77
ClinPred		0.015	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2230641; hg19: chr5-86695274; COSMIC: COSV56924372; COSMIC: COSV56924372;