rs3217980

Variant names:

• chr9-22006608-G-A
• rs3217980
• NM_004936.4:c.157-361C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000276925.7(CDKN2B):​c.157-361C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 152,146 control chromosomes in the GnomAD database, including 374 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 0.042 (374 hom., cov: 33)
• Consequence: CDKN2B ENST00000276925.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.174
• Publications: 5 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000276925.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2B	NM_004936.4	MANE Select	c.157-361C>T		intron	N/A	NP_004927.2
	CDKN2B-AS1	NR_003529.4	MANE Select	n.371+11447G>A		intron	N/A
	CDKN2B	NM_078487.2		c.*43-361C>T		intron	N/A	NP_511042.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2B	ENST00000276925.7	TSL:1 MANE Select	c.157-361C>T		intron	N/A	ENSP00000276925.6
	CDKN2B-AS1	ENST00000428597.7	TSL:1 MANE Select	n.371+11447G>A		intron	N/A
	CDKN2B	ENST00000380142.5	TSL:1	c.*43-361C>T		intron	N/A	ENSP00000369487.4

Frequencies

GnomAD3 genomes AF: 0.0421 AC: 6405 AN: 152028 Hom.: 373 Cov.: 33

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00666

Gnomad OTH AF: 0.0364

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0422 AC: 6418 AN: 152146 Hom.: 374 Cov.: 33 AF XY: 0.0411 AC XY: 3057 AN XY: 74380

African (AFR) AF: 0.131 AC: 5447 AN: 41470

American (AMR) AF: 0.0213 AC: 326 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4822

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10576

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00666 AC: 453 AN: 68010

Other (OTH) AF: 0.0360 AC: 76 AN: 2110

Alfa AF: 0.0247 Hom.: 94

Bravo AF: 0.0470

Asia WGS AF: 0.0110 AC: 39 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.1
DANN	Benign	0.61
PhyloP100		0.17
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: rs3217980; hg19: chr9-22006607;