Genetic Variant CIP2A:p.Met678Leu (chr3-108557396-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020890.3(CIP2A):c.2032A>C(p.Met678Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000388 in 1,597,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

CIP2A
NM_020890.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.20

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045728445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIP2A	NM_020890.3 link	c.2032A>C	p.Met678Leu	missense_variant	Exon 17 of 21	ENST00000295746.13	NP_065941.2	Q8TCG1-1
CIP2A	XM_006713716.4 link	c.2029A>C	p.Met677Leu	missense_variant	Exon 17 of 21		XP_006713779.1
CIP2A	XM_011513057.3 link	c.1090A>C	p.Met364Leu	missense_variant	Exon 10 of 14		XP_011511359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CIP2A	ENST00000295746.13 link	c.2032A>C	p.Met678Leu	missense_variant	Exon 17 of 21	1	NM_020890.3	ENSP00000295746.7	Q8TCG1-1
CIP2A	ENST00000491772.5 link	c.1555A>C	p.Met519Leu	missense_variant	Exon 17 of 21	1		ENSP00000419487.1	Q8TCG1-2
CIP2A	ENST00000481530.5 link	n.*1602A>C		non_coding_transcript_exon_variant	Exon 17 of 21	1		ENSP00000417297.1	F8WAX6
CIP2A	ENST00000481530.5 link	n.*1602A>C		3_prime_UTR_variant	Exon 17 of 21	1		ENSP00000417297.1	F8WAX6

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

151798

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000224

AC:

AN:

240896

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

130408

show subpopulations

Gnomad AFR exome

AF:

0.0000625

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000483

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000404

AC:

584

AN:

1446036

Hom.:

Cov.:

AF XY:

0.000373

AC XY:

268

AN XY:

718784

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000514

Gnomad4 OTH exome

AF:

0.000269

GnomAD4 genome

AF:

0.000237

AC:

AN:

151798

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74148

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000508

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000231

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2032A>C (p.M678L) alteration is located in exon 17 (coding exon 17) of the KIAA1524 gene. This alteration results from a A to C substitution at nucleotide position 2032, causing the methionine (M) at amino acid position 678 to be replaced by a leucine (L). 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

Benign

0.13

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.0021

T;.;T

Eigen

Benign

-0.26

Eigen_PC

Benign

0.0065

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.81

T;T;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.046

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.29

N;N;.

REVEL

Benign

0.13

Sift

Benign

0.74

T;T;.

Sift4G

Benign

0.97

T;T;T

Polyphen

0.011

B;.;.

Vest4

0.30

MutPred

0.34

Gain of glycosylation at S677 (P = 0.0181);.;.;

MVP

0.39

MPC

0.14

ClinPred

0.061

GERP RS

5.9

Varity_R

0.13

gMVP

0.19

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over