rs3217989

Positions:

• chr9-22003791-T-C

Variant summary

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

The NM_004936.4(CDKN2B):​c.*2196A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 232,192 control chromosomes in the GnomAD database, including 1,295 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 0.069 (1185 hom., cov: 32)
  • Exomes 𝑓: 0.016 (110 hom.)
• Consequence: CDKN2B NM_004936.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.268

Genes affected

CDKN2B (HGNC:1788): (cyclin dependent kinase inhibitor 2B) This gene lies adjacent to the tumor suppressor gene CDKN2A in a region that is frequently mutated and deleted in a wide variety of tumors. This gene encodes a cyclin-dependent kinase inhibitor, which forms a complex with CDK4 or CDK6, and prevents the activation of the CDK kinases, thus the encoded protein functions as a cell growth regulator that controls cell cycle G1 progression. The expression of this gene was found to be dramatically induced by TGF beta, which suggested its role in the TGF beta induced growth inhibition. Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported. [provided by RefSeq, Jul 2008]

CDKN2B-AS1 (HGNC:34341): (CDKN2B antisense RNA 1) This gene is located within the CDKN2B-CDKN2A gene cluster at chromosome 9p21. The gene product is a functional RNA molecule that interacts with polycomb repressive complex-1 (PRC1) and -2 (PRC2), leading to epigenetic silencing of other genes in this cluster. This region is a significant genetic susceptibility locus for cardiovascular disease, and has also been linked to a number of other pathologies, including several cancers, intracranial aneurysm, type-2 diabetes, periodontitis, Alzheimer's disease, endometriosis, frailty in the elderly, and glaucoma. Multiple alternatively processed transcript variants have been detected, some of which may take the form of circular RNA molecules (PMID:21151960). [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2B	NM_004936.4	c.*2196A>G		3_prime_UTR_variant	2/2	ENST00000276925.7	NP_004927.2
CDKN2B-AS1	NR_003529.3	n.371+8630T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2B	ENST00000276925.7	c.*2196A>G		3_prime_UTR_variant	2/2	1	NM_004936.4	ENSP00000276925	P1
CDKN2B-AS1	ENST00000650946.1	n.29+8630T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0686 AC: 10416 AN: 151938 Hom.: 1178 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.0559

GnomAD4 exome AF: 0.0163 AC: 1307 AN: 80136 Hom.: 110 Cov.: 0 AF XY: 0.0144 AC XY: 532 AN XY: 36848

Gnomad4 AFR exome AF: 0.238

Gnomad4 AMR exome AF: 0.0274

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00145

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00230

Gnomad4 OTH exome AF: 0.0276

GnomAD4 genome AF: 0.0688 AC: 10457 AN: 152056 Hom.: 1185 Cov.: 32 AF XY: 0.0658 AC XY: 4893 AN XY: 74338

Gnomad4 AFR AF: 0.235

Gnomad4 AMR AF: 0.0314

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.0553

Alfa AF: 0.0684 Hom.: 134

Bravo AF: 0.0790

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.8
DANN	Benign	0.79

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: rs3217989; hg19: chr9-22003790;