rs4135239

Positions:

• chr6-36678576-G-C

Variant summary

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

The NM_001291549.3(CDKN1A):​c.97+643G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 816,664 control chromosomes in the GnomAD database, including 6,305 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 0.11 (1093 hom., cov: 32)
  • Exomes 𝑓: 0.12 (5212 hom.)
• Consequence: CDKN1A NM_001291549.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.259

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]

DINOL (HGNC:53146): (damage induced long noncoding RNA)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DINOL	NR_144384.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1A	ENST00000448526.6	c.-6+643G>C		intron_variant		3		P1
CDKN1A	ENST00000615513.4	c.-6+2052G>C		intron_variant		2		P1
CDKN1A	ENST00000459970.1	n.189+643G>C		intron_variant, non_coding_transcript_variant		5
DINOL	ENST00000643333.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17096 AN: 152066 Hom.: 1093 Cov.: 32

Gnomad AFR AF: 0.0716

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.0511

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.122 AC: 81253 AN: 664480 Hom.: 5212 Cov.: 8 AF XY: 0.122 AC XY: 37617 AN XY: 309094

Gnomad4 AFR exome AF: 0.0610

Gnomad4 AMR exome AF: 0.0990

Gnomad4 ASJ exome AF: 0.201

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.0575

Gnomad4 FIN exome AF: 0.150

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.112 AC: 17097 AN: 152184 Hom.: 1093 Cov.: 32 AF XY: 0.115 AC XY: 8527 AN XY: 74410

Gnomad4 AFR AF: 0.0715

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.107

Gnomad4 SAS AF: 0.0507

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.112

Alfa AF: 0.130 Hom.: 191

Bravo AF: 0.109

Asia WGS AF: 0.0700 AC: 243 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.2
DANN	Benign	0.68

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: rs4135239; hg19: chr6-36646353; COSMIC: COSV55191786; COSMIC: COSV55191786;