Genetic Variant CDK2AP1:c.*474C>A (chr12-123261262-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004642.4(CDK2AP1):c.*474C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 153,260 control chromosomes in the GnomAD database, including 2,365 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 2347 hom., cov: 32)

Exomes 𝑓: 0.16 ( 18 hom. )

Consequence

CDK2AP1
NM_004642.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.09

Publications

23 publications found

Variant links:

Genes affected

CDK2AP1 (HGNC:14002): (cyclin dependent kinase 2 associated protein 1) The protein encoded by this gene is a cyclin-dependent kinase 2 (CDK2) -associated protein which is thought to negatively regulate CDK2 activity by sequestering monomeric CDK2, and targeting CDK2 for proteolysis. This protein was found to also interact with DNA polymerase alpha/primase and mediate the phosphorylation of the large p180 subunit, which suggests a regulatory role in DNA replication during the S-phase of the cell cycle. This protein also forms a core subunit of the nucleosome remodeling and histone deacetylation (NURD) complex that epigenetically regulates embryonic stem cell differentiation. This gene thus plays a role in both cell-cycle and epigenetic regulation. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2012]

CDK2AP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004642.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CDK2AP1	NM_004642.4	MANE Select	c.*474C>A	3_prime_UTR	Exon 4 of 4	NP_004633.1
CDK2AP1	NR_073007.2		n.851C>A	non_coding_transcript_exon	Exon 4 of 4
CDK2AP1	NR_073008.2		n.1132C>A	non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CDK2AP1	ENST00000261692.7	TSL:1 MANE Select	c.*474C>A	3_prime_UTR	Exon 4 of 4	ENSP00000261692.2
CDK2AP1	ENST00000541002.7	TSL:5	n.222C>A	non_coding_transcript_exon	Exon 1 of 5
CDK2AP1	ENST00000652466.1		n.*474C>A	non_coding_transcript_exon	Exon 4 of 7	ENSP00000498286.1

Frequencies

GnomAD3 genomes

AF:

0.162

AC:

24701

AN:

152030

Hom.:

2339

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0826

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.182

Gnomad ASJ

AF:

0.249

Gnomad EAS

AF:

0.00423

Gnomad SAS

AF:

0.216

Gnomad FIN

AF:

0.224

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.200

Gnomad OTH

AF:

0.172

GnomAD4 exome

AF:

0.162

AC:

180

AN:

1112

Hom.:

Cov.:

AF XY:

0.177

AC XY:

AN XY:

554

show subpopulations

African (AFR)

AF:

0.125

AC:

AN:

American (AMR)

AF:

0.151

AC:

AN:

152

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.250

AC:

AN:

European-Finnish (FIN)

AF:

0.100

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.157

AC:

122

AN:

776

Other (OTH)

AF:

0.167

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.162

AC:

24708

AN:

152148

Hom.:

2347

Cov.:

AF XY:

0.164

AC XY:

12232

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0823

AC:

3416

AN:

41522

American (AMR)

AF:

0.183

AC:

2785

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.249

AC:

864

AN:

3468

East Asian (EAS)

AF:

0.00424

AC:

AN:

5186

South Asian (SAS)

AF:

0.217

AC:

1047

AN:

4824

European-Finnish (FIN)

AF:

0.224

AC:

2370

AN:

10580

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.200

AC:

13612

AN:

67994

Other (OTH)

AF:

0.170

AC:

358

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1038

2077

3115

4154

5192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

278

556

834

1112

1390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.132

Hom.:

347

Bravo

AF:

0.155

Asia WGS

AF:

0.101

AC:

352

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over