NM_004936.4:c.*2763G>A

Variant names:

• chr9-22003224-C-T
• rs3217992
• NM_004936.4:c.*2763G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004936.4(CDKN2B):​c.*2763G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 216,292 control chromosomes in the GnomAD database, including 14,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (9107 hom., cov: 33)
  • Exomes 𝑓: 0.40 (5282 hom.)
• Consequence: CDKN2B NM_004936.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.729
• Publications: 139 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-22003224-C-T is Benign according to our data. Variant chr9-22003224-C-T is described in ClinVar as Benign. ClinVar VariationId is 812647.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004936.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2B	NM_004936.4	MANE Select	c.*2763G>A		3_prime_UTR	Exon 2 of 2	NP_004927.2
	CDKN2B-AS1	NR_003529.4	MANE Select	n.371+8063C>T		intron	N/A
	CDKN2B	NM_078487.2		c.*3066G>A		3_prime_UTR	Exon 2 of 2	NP_511042.1	P42772-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2B	ENST00000276925.7	TSL:1 MANE Select	c.*2763G>A		3_prime_UTR	Exon 2 of 2	ENSP00000276925.6	P42772-1
	CDKN2B-AS1	ENST00000428597.7	TSL:1 MANE Select	n.371+8063C>T		intron	N/A
	CDKN2B-AS1	ENST00000455933.8	TSL:1	n.340+8063C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49310 AN: 151616 Hom.: 9116 Cov.: 33

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.388

GnomAD4 exome AF: 0.397 AC: 25624 AN: 64558 Hom.: 5282 Cov.: 0 AF XY: 0.401 AC XY: 11952 AN XY: 29796

African (AFR) AF: 0.129 AC: 399 AN: 3082

American (AMR) AF: 0.335 AC: 657 AN: 1962

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1997 AN: 4054

East Asian (EAS) AF: 0.523 AC: 4818 AN: 9204

South Asian (SAS) AF: 0.401 AC: 226 AN: 564

European-Finnish (FIN) AF: 0.396 AC: 19 AN: 48

Middle Eastern (MID) AF: 0.497 AC: 186 AN: 374

European-Non Finnish (NFE) AF: 0.383 AC: 15274 AN: 39882

Other (OTH) AF: 0.380 AC: 2048 AN: 5388

GnomAD4 genome AF: 0.325 AC: 49305 AN: 151734 Hom.: 9107 Cov.: 33 AF XY: 0.327 AC XY: 24274 AN XY: 74148

African (AFR) AF: 0.141 AC: 5822 AN: 41430

American (AMR) AF: 0.378 AC: 5772 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1782 AN: 3468

East Asian (EAS) AF: 0.515 AC: 2657 AN: 5160

South Asian (SAS) AF: 0.432 AC: 2082 AN: 4820

European-Finnish (FIN) AF: 0.388 AC: 4087 AN: 10536

Middle Eastern (MID) AF: 0.534 AC: 155 AN: 290

European-Non Finnish (NFE) AF: 0.380 AC: 25761 AN: 67748

Other (OTH) AF: 0.384 AC: 809 AN: 2108

Alfa AF: 0.369 Hom.: 46730

Bravo AF: 0.314

Asia WGS AF: 0.415 AC: 1442 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Three Vessel Coronary Disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.85
DANN	Benign	0.64
PhyloP100		-0.73
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: rs3217992; hg19: chr9-22003223;