rs3829963

Positions:

• chr6-36676609-C-A

Variant summary

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

The NM_001291549.3(CDKN1A):​c.-142+39C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 152,110 control chromosomes in the GnomAD database, including 4,076 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 0.21 (4074 hom., cov: 32)
  • Exomes 𝑓: 0.24 (2 hom.)
• Consequence: CDKN1A NM_001291549.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.111

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 = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN1A	NM_001220777.2	c.-6+85C>A		intron_variant			NP_001207706.1
CDKN1A	NM_001291549.3	c.-142+39C>A		intron_variant			NP_001278478.1
CDKN1A	NM_001374509.1	c.-50+39C>A		intron_variant			NP_001361438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN1A	ENST00000448526.6	c.-38+85C>A		intron_variant		3		ENSP00000409259	P1
CDKN1A	ENST00000615513.4	c.-6+85C>A		intron_variant		2		ENSP00000482768	P1
CDKN1A	ENST00000459970.1	n.43+39C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31664 AN: 151956 Hom.: 4065 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.0830

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.199

GnomAD4 exome AF: 0.237 AC: 9 AN: 38 Hom.: 2 Cov.: 0 AF XY: 0.214 AC XY: 6 AN XY: 28

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.208

GnomAD4 genome AF: 0.208 AC: 31706 AN: 152072 Hom.: 4074 Cov.: 32 AF XY: 0.209 AC XY: 15568 AN XY: 74334

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.302

Gnomad4 ASJ AF: 0.0830

Gnomad4 EAS AF: 0.410

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.198

Alfa AF: 0.147 Hom.: 1093

Bravo AF: 0.234

Asia WGS AF: 0.245 AC: 851 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	5.3
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3829963; hg19: chr6-36644386;