Genetic Variant NM_020890.3:c.1984C>A (chr3-108559786-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020890.3(CIP2A):c.1984C>A(p.Arg662Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000697 in 1,435,504 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R662H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CIP2A
NM_020890.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.90

Publications

0 publications found

Variant links:

Genes affected

CIP2A (HGNC:29302): (cellular inhibitor of PP2A) Enables protein homodimerization activity. Predicted to act upstream of or within positive regulation of neural precursor cell proliferation and spermatogenesis. Located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CIP2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020890.3. 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
	CIP2A	NM_020890.3	MANE Select	c.1984C>A	p.Arg662Ser	missense	Exon 16 of 21	NP_065941.2	Q8TCG1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CIP2A	ENST00000295746.13	TSL:1 MANE Select	c.1984C>A	p.Arg662Ser	missense	Exon 16 of 21	ENSP00000295746.7	Q8TCG1-1
CIP2A	ENST00000491772.5	TSL:1	c.1507C>A	p.Arg503Ser	missense	Exon 16 of 21	ENSP00000419487.1	Q8TCG1-2
CIP2A	ENST00000481530.5	TSL:1	n.*1554C>A		non_coding_transcript_exon	Exon 16 of 21	ENSP00000417297.1	F8WAX6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1435504

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709796

show subpopulations

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

African (AFR)

AF:

0.0000303

AC:

AN:

33034

American (AMR)

AF:

0.00

AC:

AN:

43978

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25734

East Asian (EAS)

AF:

0.00

AC:

AN:

39036

South Asian (SAS)

AF:

0.00

AC:

AN:

83440

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092588

Other (OTH)

AF:

0.00

AC:

AN:

59134

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.096

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

5.9

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.29

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.81

MutPred

0.46

Gain of glycosylation at T666 (P = 0.0154)

MVP

0.61

MPC

0.68

ClinPred

0.96

GERP RS

6.0

Varity_R

0.60

gMVP

0.64

Mutation Taster

=16/84

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over