chr3-108554425-T-C

Variant names:

• chr3-108554425-T-C
• rs13071874
• NM_020890.3:c.2275A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020890.3(CIP2A):​c.2275A>G​(p.Ile759Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00921 in 1,567,210 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0085 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0093 (101 hom.)
• Consequence: CIP2A NM_020890.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.574

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028879046).
• BP6: Variant 3-108554425-T-C is Benign according to our data. Variant chr3-108554425-T-C is described in ClinVar as [Benign]. Clinvar id is 2654025.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00929 (13143/1414870) while in subpopulation MID AF= 0.0282 (153/5430). AF 95% confidence interval is 0.0245. There are 101 homozygotes in gnomad4_exome. There are 6722 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIP2A	NM_020890.3	c.2275A>G	p.Ile759Val	missense_variant	Exon 18 of 21	ENST00000295746.13	NP_065941.2
CIP2A	XM_006713716.4	c.2272A>G	p.Ile758Val	missense_variant	Exon 18 of 21		XP_006713779.1
CIP2A	XM_011513057.3	c.1333A>G	p.Ile445Val	missense_variant	Exon 11 of 14		XP_011511359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIP2A	ENST00000295746.13	c.2275A>G	p.Ile759Val	missense_variant	Exon 18 of 21	1	NM_020890.3	ENSP00000295746.7
CIP2A	ENST00000491772.5	c.1798A>G	p.Ile600Val	missense_variant	Exon 18 of 21	1		ENSP00000419487.1
CIP2A	ENST00000481530.5	n.*1845A>G		non_coding_transcript_exon_variant	Exon 18 of 21	1		ENSP00000417297.1
CIP2A	ENST00000481530.5	n.*1845A>G		3_prime_UTR_variant	Exon 18 of 21	1		ENSP00000417297.1

Frequencies

GnomAD3 genomes AF: 0.00849 AC: 1293 AN: 152222 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.00977 AC: 2276 AN: 233056 Hom.: 17 AF XY: 0.0106 AC XY: 1327 AN XY: 125374

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00759

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00997

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.00929 AC: 13143 AN: 1414870 Hom.: 101 Cov.: 24 AF XY: 0.00954 AC XY: 6722 AN XY: 704944

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00823

Gnomad4 ASJ exome AF: 0.0216

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.00922

Gnomad4 OTH exome AF: 0.00973

GnomAD4 genome AF: 0.00849 AC: 1293 AN: 152340 Hom.: 8 Cov.: 31 AF XY: 0.00860 AC XY: 641 AN XY: 74506

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0112 Hom.: 22

Bravo AF: 0.00830

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0112 AC: 96

ExAC AF: 0.00899 AC: 1090

Asia WGS AF: 0.00578 AC: 20 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

CIP2A: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.0032	T;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.73	T;T;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.16	N;N;.
REVEL	Benign	0.11
Sift	Benign	0.67	T;T;.
Sift4G	Benign	0.36	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.051
MVP		0.41
MPC		0.12
ClinPred		0.0057	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.049

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

Publications

LitVar

Other links and lift over

dbSNP: rs13071874; hg19: chr3-108273272; COSMIC: COSV99041334;