Genetic Variant CDKN1A:c.445+16C>G (chr6-36684562-C-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001374511.1(CDKN1A):c.461C>G(p.Thr154Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,610,990 control chromosomes in the GnomAD database, including 87,473 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

Frequency

Genomes: 𝑓 0.40 ( 14215 hom., cov: 32)

Exomes 𝑓: 0.30 ( 73258 hom. )

Consequence

CDKN1A
NM_001374511.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.00

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 6-36684562-C-G is Benign according to our data. Variant chr6-36684562-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1A	NM_000389.5 link	c.445+16C>G		intron_variant	Intron 2 of 2	ENST00000244741.10	NP_000380.1	P38936A0A024RCX5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1A	ENST00000244741.10 link	c.445+16C>G		intron_variant	Intron 2 of 2	1	NM_000389.5	ENSP00000244741.6		P38936

Frequencies

GnomAD3 genomes

AF:

0.400

AC:

60710

AN:

151892

Hom.:

14168

Cov.:

show subpopulations

Gnomad AFR

AF:

0.629

Gnomad AMI

AF:

0.289

Gnomad AMR

AF:

0.433

Gnomad ASJ

AF:

0.335

Gnomad EAS

AF:

0.612

Gnomad SAS

AF:

0.432

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.265

Gnomad OTH

AF:

0.416

GnomAD3 exomes

AF:

0.366

AC:

90909

AN:

248658

Hom.:

19002

AF XY:

0.358

AC XY:

48223

AN XY:

134630

show subpopulations

Gnomad AFR exome

AF:

0.640

Gnomad AMR exome

AF:

0.489

Gnomad ASJ exome

AF:

0.352

Gnomad EAS exome

AF:

0.596

Gnomad SAS exome

AF:

0.414

Gnomad FIN exome

AF:

0.228

Gnomad NFE exome

AF:

0.267

Gnomad OTH exome

AF:

0.335

GnomAD4 exome

AF:

0.300

AC:

438142

AN:

1458980

Hom.:

73258

Cov.:

AF XY:

0.303

AC XY:

219932

AN XY:

725948

show subpopulations

Gnomad4 AFR exome

AF:

0.639

Gnomad4 AMR exome

AF:

0.482

Gnomad4 ASJ exome

AF:

0.351

Gnomad4 EAS exome

AF:

0.624

Gnomad4 SAS exome

AF:

0.418

Gnomad4 FIN exome

AF:

0.228

Gnomad4 NFE exome

AF:

0.262

Gnomad4 OTH exome

AF:

0.340

GnomAD4 genome

AF:

0.400

AC:

60816

AN:

152010

Hom.:

14215

Cov.:

AF XY:

0.400

AC XY:

29711

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.629

Gnomad4 AMR

AF:

0.433

Gnomad4 ASJ

AF:

0.335

Gnomad4 EAS

AF:

0.612

Gnomad4 SAS

AF:

0.431

Gnomad4 FIN

AF:

0.231

Gnomad4 NFE

AF:

0.265

Gnomad4 OTH

AF:

0.423

Alfa

AF:

0.236

Hom.:

845

Bravo

AF:

0.430

Asia WGS

AF:

0.537

AC:

1865

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

DANN

Benign

0.64

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