chr5-132750975-C-T

Variant names:

• chr5-132750975-C-T
• rs749993881
• NM_001039780.4:c.752C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001039780.4(CCNI2):​c.752C>T​(p.Thr251Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T251T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CCNI2 NM_001039780.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04
• Publications: 2 publications found

Genes affected

CCNI2 (HGNC:33869): (cyclin I family member 2) Predicted to enable cyclin-dependent protein serine/threonine kinase regulator activity. Predicted to be involved in mitotic cell cycle phase transition and regulation of cyclin-dependent protein serine/threonine kinase activity. Predicted to be part of cyclin-dependent protein kinase holoenzyme complex. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SEPTIN8 (HGNC:16511): (septin 8) This gene is a member of the septin family of nucleotide binding proteins, originally described in yeast as cell division cycle regulatory proteins. Septins are highly conserved in yeast, Drosophila, and mouse, and appear to regulate cytoskeletal organization. Disruption of septin function disturbs cytokinesis and results in large multinucleate or polyploid cells. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039780.4. 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
	CCNI2	NM_001039780.4	MANE Select	c.752C>T	p.Thr251Met	missense	Exon 4 of 6	NP_001034869.1	Q6ZMN8-1
	SEPTIN8	NM_001098811.2	MANE Select	c.*1041G>A		3_prime_UTR	Exon 10 of 10	NP_001092281.1	Q92599-1
	CCNI2	NM_001287252.2		c.752C>T	p.Thr251Met	missense	Exon 4 of 6	NP_001274181.1	Q6ZMN8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCNI2	ENST00000378731.6	TSL:1 MANE Select	c.752C>T	p.Thr251Met	missense	Exon 4 of 6	ENSP00000368005.1	Q6ZMN8-1
	CCNI2	ENST00000614847.1	TSL:1	c.752C>T	p.Thr251Met	missense	Exon 4 of 6	ENSP00000478257.1	Q6ZMN8-2
	SEPTIN8	ENST00000378719.7	TSL:1 MANE Select	c.*1041G>A		3_prime_UTR	Exon 10 of 10	ENSP00000367991.2	Q92599-1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000717 AC: 18 AN: 250948 AF XY: 0.0000590

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461658 Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21 AN XY: 727120

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.000224 AC: 10 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86186

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74386

African (AFR) AF: 0.0000724 AC: 3 AN: 41462

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

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

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5198

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000576 AC: 7

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	Benign	0.28
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.0
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.65		Loss of catalytic residue at T251 (P = 0.1663)
MVP		0.53
MPC		0.70
ClinPred		0.84	D
GERP RS		2.4
Varity_R		0.60
gMVP		0.81
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs749993881; hg19: chr5-132086667;