Genetic Variant CDKN1A:c.97+643G>A (chr6-36678576-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001291549.3(CDKN1A):c.97+643G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 665,396 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

CDKN1A
NM_001291549.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.259

Publications

0 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:

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

DINOL links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291549.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
CDKN1A	NM_001291549.3	c.97+643G>A	intron	N/A	NP_001278478.1
CDKN1A	NM_001374509.1	c.97+643G>A	intron	N/A	NP_001361438.1
CDKN1A	NM_001374510.1	c.34+2006G>A	intron	N/A	NP_001361439.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CDKN1A	ENST00000448526.6	TSL:3	c.-6+643G>A	intron	N/A	ENSP00000409259.3
CDKN1A	ENST00000615513.4	TSL:2	c.-6+2052G>A	intron	N/A	ENSP00000482768.1
CDKN1A	ENST00000864199.1		c.-6+2006G>A	intron	N/A	ENSP00000534258.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000150

AC:

AN:

665396

Hom.:

Cov.:

AF XY:

0.00000323

AC XY:

AN XY:

309518

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

12670

American (AMR)

AF:

0.00

AC:

AN:

798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4092

East Asian (EAS)

AF:

0.00

AC:

AN:

2846

South Asian (SAS)

AF:

0.00

AC:

AN:

13318

European-Finnish (FIN)

AF:

0.00

AC:

AN:

220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1330

European-Non Finnish (NFE)

AF:

0.00000164

AC:

AN:

608388

Other (OTH)

AF:

0.00

AC:

AN:

21734

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.8

(source)

DANN

Benign

0.90

PhyloP100

-0.26

PromoterAI

0.019

Neutral

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over