9-22003224-C-T

Position:

• chr9-22003224-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2B	NM_004936.4	c.*2763G>A		3_prime_UTR_variant	2/2	ENST00000276925.7
CDKN2B-AS1	NR_003529.3	n.371+8063C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2B	ENST00000276925.7	c.*2763G>A		3_prime_UTR_variant	2/2	1	NM_004936.4	P1
CDKN2B-AS1	ENST00000650946.1	n.29+8063C>T		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.335

Gnomad4 ASJ exome AF: 0.493

Gnomad4 EAS exome AF: 0.523

Gnomad4 SAS exome AF: 0.401

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.383

Gnomad4 OTH exome AF: 0.380

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

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.378

Gnomad4 ASJ AF: 0.514

Gnomad4 EAS AF: 0.515

Gnomad4 SAS AF: 0.432

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.384

Alfa AF: 0.385 Hom.: 25038

Bravo AF: 0.314

Asia WGS AF: 0.415 AC: 1442 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Three Vessel Coronary Disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Cardiology, Chinese Academy of Medical Sciences, Fuwai Hospital

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.85
DANN	Benign	0.64

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: rs3217992; hg19: chr9-22003223;