rs3176343

Positions:

• chr6-36682490-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000389.5(CDKN1A):​c.-5-1607G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0884 in 152,264 control chromosomes in the GnomAD database, including 819 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 0.088 (819 hom., cov: 32)
  • Exomes 𝑓: 0.058 (0 hom.)
• Consequence: CDKN1A NM_000389.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1A	NM_000389.5	c.-5-1607G>A		intron_variant		ENST00000244741.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1A	ENST00000244741.10	c.-5-1607G>A		intron_variant		1	NM_000389.5	P1

Frequencies

GnomAD3 genomes AF: 0.0885 AC: 13458 AN: 152094 Hom.: 825 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0894

Gnomad ASJ AF: 0.0734

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0339

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0524

Gnomad OTH AF: 0.0821

GnomAD4 exome AF: 0.0577 AC: 3 AN: 52 Hom.: 0 AF XY: 0.0476 AC XY: 2 AN XY: 42

Gnomad4 AFR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 NFE exome AF: 0.0556

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0884 AC: 13460 AN: 152212 Hom.: 819 Cov.: 32 AF XY: 0.0902 AC XY: 6711 AN XY: 74430

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.0892

Gnomad4 ASJ AF: 0.0734

Gnomad4 EAS AF: 0.294

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0339

Gnomad4 NFE AF: 0.0524

Gnomad4 OTH AF: 0.0826

Alfa AF: 0.0653 Hom.: 128

Bravo AF: 0.0956

Asia WGS AF: 0.160 AC: 557 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.8
DANN	Benign	0.54

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: rs3176343; hg19: chr6-36650267;