dbSNP rs4135234: CDKN1A:c.-268G>A (chr6-36676444-G-A) – 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.-268G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.093 in 152,310 control chromosomes in the GnomAD database, including 764 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 0.093 ( 763 hom., cov: 32)

Exomes 𝑓: 0.073 ( 1 hom. )

Consequence

CDKN1A
NM_001291549.3 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.94

Publications

3 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:

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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=-0.87).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Protein	UniProt
CDKN1A	NM_001291549.3 link	c.-268G>A	upstream_gene_variant	NP_001278478.1	P38936
CDKN1A	NM_001374509.1 link	c.-176G>A	upstream_gene_variant	NP_001361438.1
CDKN1A	NM_001374510.1 link	c.-93G>A	upstream_gene_variant	NP_001361439.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	Protein	UniProt
CDKN1A	ENST00000448526.6 link	c.-118G>A	upstream_gene_variant	3	ENSP00000409259.3	P38936
CDKN1A	ENST00000615513.4 link	c.-86G>A	upstream_gene_variant	2	ENSP00000482768.1	P38936
CDKN1A	ENST00000459970.1 link	n.-84G>A	upstream_gene_variant	5

Frequencies

GnomAD3 genomes

AF:

0.0930

AC:

14151

AN:

152110

Hom.:

763

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0574

Gnomad AMI

AF:

0.0680

Gnomad AMR

AF:

0.0890

Gnomad ASJ

AF:

0.190

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.0520

Gnomad FIN

AF:

0.141

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.101

GnomAD4 exome

AF:

0.0732

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0217

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.214

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0370

AC:

AN:

Other (OTH)

AF:

0.100

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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

AF:

0.0930

AC:

14154

AN:

152228

Hom.:

763

Cov.:

AF XY:

0.0963

AC XY:

7164

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0574

AC:

2385

AN:

41538

American (AMR)

AF:

0.0890

AC:

1361

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

660

AN:

3468

East Asian (EAS)

AF:

0.109

AC:

563

AN:

5182

South Asian (SAS)

AF:

0.0518

AC:

250

AN:

4826

European-Finnish (FIN)

AF:

0.141

AC:

1488

AN:

10584

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.105

AC:

7139

AN:

68026

Other (OTH)

AF:

0.100

AC:

211

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

670

1340

2011

2681

3351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.0947

Hom.:

523

Bravo

AF:

0.0892

Asia WGS

AF:

0.0670

AC:

233

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.3

(source)

DANN

Benign

0.36

PhyloP100

-1.9

PromoterAI

-0.097

Neutral

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over