4-77159485-G-C

Position:

• chr4-77159485-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004354.3(CCNG2):​c.257G>C​(p.Arg86Thr) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCNG2 NM_004354.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

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]

CCNG2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCNG2	NM_004354.3	c.257G>C	p.Arg86Thr	missense_variant	3/8	ENST00000316355.10	NP_004345.1
CCNG2	XM_011532398.2	c.257G>C	p.Arg86Thr	missense_variant	3/8		XP_011530700.1
CCNG2	XM_011532399.3	c.257G>C	p.Arg86Thr	missense_variant	3/8		XP_011530701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCNG2	ENST00000316355.10	c.257G>C	p.Arg86Thr	missense_variant	3/8	1	NM_004354.3	ENSP00000315743.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

May 09, 2022

The c.257G>C (p.R86T) alteration is located in exon 3 (coding exon 2) of the CCNG2 gene. This alteration results from a G to C substitution at nucleotide position 257, causing the arginine (R) at amino acid position 86 to be replaced by a threonine (T). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;T;T;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;.;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	3.4	M;M;M;.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.0	D;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.96
MutPred		0.88		Loss of MoRF binding (P = 0.1035);Loss of MoRF binding (P = 0.1035);Loss of MoRF binding (P = 0.1035);Loss of MoRF binding (P = 0.1035);Loss of MoRF binding (P = 0.1035);
MVP		0.82
MPC		1.0
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-78080638;