6-36684562-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000389.5(CDKN1A):c.445+16C>G variant causes a intron 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. 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_000389.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00

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]

ACMG classification

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/exons	MANE	UniProt
CDKN1A	NM_000389.5	c.445+16C>G		intron_variant		ENST00000244741.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1A	ENST00000244741.10	c.445+16C>G		intron_variant		1	NM_000389.5	P1

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60710 AN: 151892 Hom.: 14168 Cov.: 32

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

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.: 32 AF XY: 0.303 AC XY: 219932 AN XY: 725948

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.: 32 AF XY: 0.400 AC XY: 29711 AN XY: 74324

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	12
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

Other links and lift over

dbSNP: rs3176352; hg19: chr6-36652339; COSMIC: COSV55189067; COSMIC: COSV55189067;