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

Variant summary

Our verdict is Benign. Variant got -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 made for transcript

Verdict is Benign. Variant got -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

Gnomad4 AFR exome

AF:

0.319

Gnomad4 AMR exome

AF:

0.200

Gnomad4 ASJ exome

AF:

0.289

Gnomad4 EAS exome

AF:

0.143

Gnomad4 SAS exome

AF:

0.329

Gnomad4 FIN exome

AF:

0.210

Gnomad4 NFE exome

AF:

0.230

Gnomad4 OTH exome

AF:

0.254

GnomAD4 genome

AF:

0.218

AC:

33145

AN:

152076

Hom.:

3667

Cov.:

AF XY:

0.217

AC XY:

16111

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.260

Gnomad4 AMR

AF:

0.198

Gnomad4 ASJ

AF:

0.264

Gnomad4 EAS

AF:

0.129

Gnomad4 SAS

AF:

0.300

Gnomad4 FIN

AF:

0.179

Gnomad4 NFE

AF:

0.202

Gnomad4 OTH

AF:

0.260

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

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