rs4135234

Positions:

• chr6-36676444-G-A
• chr6-36676444-G-T

Variant summary

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

The 6-36676444-G-A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.093 in 152,310 control chromosomes in the GnomAD database, including 764 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 0.093 (763 hom., cov: 32)
  • Exomes 𝑓: 0.073 (1 hom.)
• Consequence: CDKN1A NM_001291549.3 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.94

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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1A	NM_001220777.2			upstream_gene_variant
CDKN1A	NM_001291549.3			upstream_gene_variant
CDKN1A	NM_001374509.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1A	ENST00000448526.6			upstream_gene_variant		3		P1
CDKN1A	ENST00000615513.4			upstream_gene_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.0930 AC: 14151 AN: 152110 Hom.: 763 Cov.: 32

Gnomad AFR AF: 0.0574

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0890

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0520

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.101

GnomAD4 exome AF: 0.0732 AC: 6 AN: 82 Hom.: 1 Cov.: 0 AF XY: 0.0217 AC XY: 1 AN XY: 46

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.214

Gnomad4 NFE exome AF: 0.0370

Gnomad4 OTH exome AF: 0.100

GnomAD4 genome AF: 0.0930 AC: 14154 AN: 152228 Hom.: 763 Cov.: 32 AF XY: 0.0963 AC XY: 7164 AN XY: 74416

Gnomad4 AFR AF: 0.0574

Gnomad4 AMR AF: 0.0890

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.0518

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.100

Alfa AF: 0.0832 Hom.: 225

Bravo AF: 0.0892

Asia WGS AF: 0.0670 AC: 233 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.3
DANN	Benign	0.36

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4135234; hg19: chr6-36644221;