2-134953434-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_058241.3(CCNT2):c.979A>G(p.Thr327Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,460,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CCNT2 NM_058241.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.556

Genes affected

CCNT2 (HGNC:1600): (cyclin T2) 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 and its kinase partner CDK9 were found to be subunits of the transcription elongation factor p-TEFb. The p-TEFb complex containing this cyclin was reported to interact with, and act as a negative regulator of human immunodeficiency virus type 1 (HIV-1) Tat protein. A pseudogene of this gene is found on chromosome 1. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03293395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCNT2	NM_058241.3	c.979A>G	p.Thr327Ala	missense_variant	9/9	ENST00000264157.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCNT2	ENST00000264157.10	c.979A>G	p.Thr327Ala	missense_variant	9/9	1	NM_058241.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 247908 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134098

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000554

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460030 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726280

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.979A>G (p.T327A) alteration is located in exon 9 (coding exon 9) of the CCNT2 gene. This alteration results from a A to G substitution at nucleotide position 979, causing the threonine (T) at amino acid position 327 to be replaced by an alanine (A). 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	0.059
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	13
Dann	Benign	0.87
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.22	N;N
REVEL	Benign	0.11
Sift	Benign	0.78	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0	B;B
Vest4		0.047
MutPred		0.071		Loss of phosphorylation at T327 (P = 0.048);Loss of phosphorylation at T327 (P = 0.048);
MVP		0.33
MPC		0.095
ClinPred		0.013	T
GERP RS		-1.5
Varity_R		0.057
gMVP		0.34

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: rs771733534; hg19: chr2-135711004;