9-22003791-T-C

Variant names:

• chr9-22003791-T-C
• rs3217989
• NM_004936.4:c.*2196A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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]

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CDKN2B	NM_004936.4	c.*2196A>G		3_prime_UTR_variant	Exon 2 of 2	ENST00000276925.7	NP_004927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2B	ENST00000276925.7	c.*2196A>G		3_prime_UTR_variant	Exon 2 of 2	1	NM_004936.4	ENSP00000276925.6

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

African (AFR) AF: 0.238 AC: 921 AN: 3864

American (AMR) AF: 0.0274 AC: 68 AN: 2486

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 8 AN: 5088

East Asian (EAS) AF: 0.00 AC: 0 AN: 11202

South Asian (SAS) AF: 0.00145 AC: 1 AN: 692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 58

Middle Eastern (MID) AF: 0.0207 AC: 10 AN: 484

European-Non Finnish (NFE) AF: 0.00230 AC: 114 AN: 49554

Other (OTH) AF: 0.0276 AC: 185 AN: 6708

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

African (AFR) AF: 0.235 AC: 9723 AN: 41450

American (AMR) AF: 0.0314 AC: 480 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00172 AC: 117 AN: 67942

Other (OTH) AF: 0.0553 AC: 117 AN: 2114

Alfa AF: 0.0447 Hom.: 197

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
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3217989; hg19: chr9-22003790;