Genetic Variant CDKN1A:p.Gly91Gly (chr6-36684374-A-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_000389.5(CDKN1A):c.273A>T(p.Gly91Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,613,176 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

CDKN1A
NM_000389.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:3

Conservation

PhyloP100: 0.118

Publications

1 publications found

Variant links:

COSMIC-nc: COSV104391880

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 6-36684374-A-T is Benign according to our data. Variant chr6-36684374-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1206063.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.118 with no splicing effect.

BS2

High AC in GnomAd4 at 46 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.273A>T	p.Gly91Gly	synonymous	Exon 2 of 3	NP_000380.1	P38936
CDKN1A	NM_001291549.3		c.375A>T	p.Gly125Gly	synonymous	Exon 3 of 4	NP_001278478.1
CDKN1A	NM_001374509.1		c.375A>T	p.Gly125Gly	synonymous	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.273A>T	p.Gly91Gly	synonymous	Exon 2 of 3	ENSP00000244741.6	P38936
CDKN1A	ENST00000405375.5	TSL:1	c.273A>T	p.Gly91Gly	synonymous	Exon 2 of 3	ENSP00000384849.1	P38936
CDKN1A	ENST00000373711.4	TSL:5	c.273A>T	p.Gly91Gly	synonymous	Exon 3 of 4	ENSP00000362815.1	P38936

Frequencies

GnomAD3 genomes

AF:

0.000303

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.000493

AC:

122

AN:

247672

AF XY:

0.000492

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000758

Gnomad ASJ exome

AF:

0.00260

Gnomad EAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.000430

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.000273

AC:

399

AN:

1460996

Hom.:

Cov.:

AF XY:

0.000294

AC XY:

214

AN XY:

726778

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33464

American (AMR)

AF:

0.000896

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.00360

AC:

AN:

26120

East Asian (EAS)

AF:

0.000302

AC:

AN:

39678

South Asian (SAS)

AF:

0.000580

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53060

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000152

AC:

169

AN:

1111766

Other (OTH)

AF:

0.000464

AC:

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000302

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41514

American (AMR)

AF:

0.000850

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68010

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000605

Hom.:

Bravo

AF:

0.000419

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.00113

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.4

(source)

DANN

Benign

0.75

PhyloP100

0.12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(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