NM_000389.5:c.350G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000389.5(CDKN1A):c.350G>A(p.Cys117Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00332 in 1,614,100 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 10 hom. )

Consequence

CDKN1A
NM_000389.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 4.09

Publications

13 publications found

Variant links:

Genes affected

CDKN1A (HGNC:1784): (cyclin dependent kinase inhibitor 1A) This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-cyclin-dependent kinase2 or -cyclin-dependent kinase4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This protein can interact with proliferating cell nuclear antigen, a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of cyclin-dependent kinase2, and may be instrumental in the execution of apoptosis following caspase activation. Mice that lack this gene have the ability to regenerate damaged or missing tissue. Multiple alternatively spliced variants have been found for this gene. [provided by RefSeq, Sep 2015]

CDKN1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.076607496).

BP6

Variant 6-36684451-G-A is Benign according to our data. Variant chr6-36684451-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 430358.

BS2

High AC in GnomAd4 at 287 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000389.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKN1A	NM_000389.5	MANE Select	c.350G>A	p.Cys117Tyr	missense	Exon 2 of 3	NP_000380.1	P38936
CDKN1A	NM_001291549.3		c.452G>A	p.Cys151Tyr	missense	Exon 3 of 4	NP_001278478.1
CDKN1A	NM_001374509.1		c.452G>A	p.Cys151Tyr	missense	Exon 3 of 4	NP_001361438.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKN1A	ENST00000244741.10	TSL:1 MANE Select	c.350G>A	p.Cys117Tyr	missense	Exon 2 of 3	ENSP00000244741.6	P38936
CDKN1A	ENST00000405375.5	TSL:1	c.350G>A	p.Cys117Tyr	missense	Exon 2 of 3	ENSP00000384849.1	P38936
CDKN1A	ENST00000373711.4	TSL:5	c.350G>A	p.Cys117Tyr	missense	Exon 3 of 4	ENSP00000362815.1	P38936

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

287

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00363

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00192

AC:

480

AN:

250376

AF XY:

0.00185

show subpopulations

Gnomad AFR exome

AF:

0.000558

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000515

Gnomad NFE exome

AF:

0.00352

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00347

AC:

5071

AN:

1461730

Hom.:

Cov.:

AF XY:

0.00336

AC XY:

2446

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33476

American (AMR)

AF:

0.00148

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.000600

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00431

AC:

4791

AN:

1111976

Other (OTH)

AF:

0.00253

AC:

153

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

308

616

925

1233

1541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

384

576

768

960

<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:

0.00188

AC:

287

AN:

152370

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41592

American (AMR)

AF:

0.000849

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00363

AC:

247

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00307

Hom.:

Bravo

AF:

0.00185

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00178

AC:

216

EpiCase

AF:

0.00278

EpiControl

AF:

0.00320

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.077

MetaSVM

Uncertain

-0.072

MutationAssessor

Benign

1.7

PhyloP100

4.1

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.42

Sift

Uncertain

0.026

Sift4G

Benign

0.097

Polyphen

0.99

Vest4

0.68

MVP

0.93

MPC

0.91

ClinPred

0.030

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.35

gMVP

0.54

Mutation Taster

=72/28

polymorphism

(source)

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

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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