chr4-77164323-T-C

Variant names:

• chr4-77164323-T-C
• NM_004354.3:c.755T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004354.3(CCNG2):​c.755T>C​(p.Leu252Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCNG2 NM_004354.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

Genes affected

CCNG2 (HGNC:1593): (cyclin G2) The eukaryotic cell cycle is governed by cyclin-dependent protein kinases (CDKs) whose activities are regulated by cyclins and CDK inhibitors. The 8 species of cyclins reported in mammals, cyclins A through H, share a conserved amino acid sequence of about 90 residues called the cyclin box. The amino acid sequence of cyclin G is well conserved among mammals. The nucleotide sequence of cyclin G1 and cyclin G2 are 53% identical. Unlike cyclin G1, cyclin G2 contains a C-terminal PEST protein destabilization motif, suggesting that cyclin G2 expression is tightly regulated through the cell cycle. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004354.3. 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
	CCNG2	NM_004354.3	MANE Select	c.755T>C	p.Leu252Pro	missense	Exon 7 of 8	NP_004345.1	Q16589-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCNG2	ENST00000316355.10	TSL:1 MANE Select	c.755T>C	p.Leu252Pro	missense	Exon 7 of 8	ENSP00000315743.5	Q16589-1
	CCNG2	ENST00000395640.5	TSL:1	c.755T>C	p.Leu252Pro	missense	Exon 6 of 7	ENSP00000379002.1	Q16589-1
	CCNG2	ENST00000497512.5	TSL:1	n.1037T>C		non_coding_transcript_exon	Exon 7 of 12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.80		Gain of disorder (P = 0.0102)
MVP		0.85
MPC		1.1
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.91
gMVP		0.88
Mutation Taster		=31/69	disease causing

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

hg19: chr4-78085476;