4-121818891-A-C

Variant names:

• chr4-121818891-A-C
• rs376488849
• NM_001237.5:c.1025T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001237.5(CCNA2):​c.1025T>G​(p.Ile342Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I342T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CCNA2 NM_001237.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.46
• Publications: 0 publications found

Genes affected

CCNA2 (HGNC:1578): (cyclin A2) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members function as regulators of the cell cycle. This protein binds and activates cyclin-dependent kinase 2 and thus promotes transition through G1/S and G2/M. [provided by RefSeq, Aug 2016]

CCNA2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001237.5. 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
	CCNA2	NM_001237.5	MANE Select	c.1025T>G	p.Ile342Arg	missense	Exon 6 of 8	NP_001228.2	P20248

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCNA2	ENST00000274026.10	TSL:1 MANE Select	c.1025T>G	p.Ile342Arg	missense	Exon 6 of 8	ENSP00000274026.5	P20248
	CCNA2	ENST00000876644.1		c.1040T>G	p.Ile347Arg	missense	Exon 6 of 8	ENSP00000546703.1
	CCNA2	ENST00000940444.1		c.1031T>G	p.Ile344Arg	missense	Exon 6 of 8	ENSP00000610503.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458626 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725904

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109060

Other (OTH) AF: 0.00 AC: 0 AN: 60282

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.69
MutPred		0.71		Loss of stability (P = 0.0075)
MVP		0.60
MPC		2.3
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.65
gMVP		0.77
Mutation Taster		=18/82	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

dbSNP: rs376488849; hg19: chr4-122740046;