Genetic Variant CDKN1A:c.97+278G>C (chr6-36678211-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001291549.3(CDKN1A):c.97+278G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 277,810 control chromosomes in the GnomAD database, including 7,018 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 0.22 ( 3667 hom., cov: 32)

Exomes 𝑓: 0.25 ( 3351 hom. )

Consequence

CDKN1A
NM_001291549.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.09

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:

DINOL (HGNC:53146): (damage induced long noncoding RNA)

DINOL 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=-0.81).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
CDKN1A	NM_001291549.3 link	c.97+278G>C	intron_variant	Intron 2 of 3	NP_001278478.1	P38936
CDKN1A	NM_001374509.1 link	c.97+278G>C	intron_variant	Intron 2 of 3	NP_001361438.1
CDKN1A	NM_001374510.1 link	c.34+1641G>C	intron_variant	Intron 1 of 2	NP_001361439.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
CDKN1A	ENST00000448526.6 link	c.-6+278G>C	intron_variant	Intron 2 of 3	3	ENSP00000409259.3	P38936
CDKN1A	ENST00000615513.4 link	c.-6+1687G>C	intron_variant	Intron 1 of 2	2	ENSP00000482768.1	P38936
DINOL	ENST00000643333.1 link	n.349C>G	non_coding_transcript_exon_variant	Exon 1 of 1
CDKN1A	ENST00000459970.1 link	n.189+278G>C	intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.218

AC:

33122

AN:

151958

Hom.:

3658

Cov.:

show subpopulations

Gnomad AFR

AF:

0.260

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.199

Gnomad ASJ

AF:

0.264

Gnomad EAS

AF:

0.129

Gnomad SAS

AF:

0.299

Gnomad FIN

AF:

0.179

Gnomad MID

AF:

0.306

Gnomad NFE

AF:

0.202

Gnomad OTH

AF:

0.252

GnomAD4 exome

AF:

0.249

AC:

31368

AN:

125734

Hom.:

3351

Cov.:

AF XY:

0.262

AC XY:

18018

AN XY:

68818

show subpopulations

African (AFR)

AF:

0.319

AC:

894

AN:

2802

American (AMR)

AF:

0.200

AC:

1016

AN:

5074

Ashkenazi Jewish (ASJ)

AF:

0.289

AC:

926

AN:

3206

East Asian (EAS)

AF:

0.143

AC:

673

AN:

4696

South Asian (SAS)

AF:

0.329

AC:

8369

AN:

25402

European-Finnish (FIN)

AF:

0.210

AC:

1083

AN:

5146

Middle Eastern (MID)

AF:

0.265

AC:

129

AN:

486

European-Non Finnish (NFE)

AF:

0.230

AC:

16655

AN:

72538

Other (OTH)

AF:

0.254

AC:

1623

AN:

6384

Heterozygous variant carriers

1058

2116

3174

4232

5290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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:

0.218

AC:

33145

AN:

152076

Hom.:

3667

Cov.:

AF XY:

0.217

AC XY:

16111

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.260

AC:

10767

AN:

41462

American (AMR)

AF:

0.198

AC:

3034

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.264

AC:

916

AN:

3470

East Asian (EAS)

AF:

0.129

AC:

665

AN:

5166

South Asian (SAS)

AF:

0.300

AC:

1445

AN:

4822

European-Finnish (FIN)

AF:

0.179

AC:

1895

AN:

10576

Middle Eastern (MID)

AF:

0.312

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.202

AC:

13723

AN:

67980

Other (OTH)

AF:

0.260

AC:

548

AN:

2110

Heterozygous variant carriers

1328

2656

3983

5311

6639

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

348

696

1044

1392

1740

<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:

0.200

Hom.:

379

Bravo

AF:

0.218

Asia WGS

AF:

0.261

AC:

911

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

7.4

DANN

Benign

0.37

Mutation Taster

=100/0

polymorphism (auto)

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over