9-22003368-G-A

Variant names:

• chr9-22003368-G-A
• rs1063192
• NM_004936.4:c.*2619C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The NM_004936.4(CDKN2B):​c.*2619C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 223,992 control chromosomes in the GnomAD database, including 55,584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,protective (no stars).

• Frequency:
  • Genomes: 𝑓 0.71 (39900 hom., cov: 33)
  • Exomes 𝑓: 0.65 (15684 hom.)
• Consequence: CDKN2B NM_004936.4 3_prime_UTR
• Clinical Significance: Likely pathogenic; protective no assertion criteria provided P:1 B:1 O:1
• Conservation: PhyloP100: -2.17
• Publications: 180 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 -8 ACMG points.

• PP5: Variant 9-22003368-G-A is Pathogenic according to our data. Variant chr9-22003368-G-A is described in ClinVar as Likely_pathogenic|protective. ClinVar VariationId is 812639.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91). . Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.916 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2B	NM_004936.4	MANE Select	c.*2619C>T		3_prime_UTR	Exon 2 of 2	NP_004927.2
	CDKN2B-AS1	NR_003529.4	MANE Select	n.371+8207G>A		intron	N/A
	CDKN2B	NM_078487.2		c.*2922C>T		3_prime_UTR	Exon 2 of 2	NP_511042.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2B	ENST00000276925.7	TSL:1 MANE Select	c.*2619C>T		3_prime_UTR	Exon 2 of 2	ENSP00000276925.6
	CDKN2B-AS1	ENST00000428597.7	TSL:1 MANE Select	n.371+8207G>A		intron	N/A
	CDKN2B-AS1	ENST00000455933.8	TSL:1	n.340+8207G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.707 AC: 107346 AN: 151824 Hom.: 39840 Cov.: 33

Gnomad AFR AF: 0.924

Gnomad AMI AF: 0.504

Gnomad AMR AF: 0.779

Gnomad ASJ AF: 0.715

Gnomad EAS AF: 0.821

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.576

Gnomad MID AF: 0.825

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.726

GnomAD4 exome AF: 0.652 AC: 46963 AN: 72050 Hom.: 15684 Cov.: 0 AF XY: 0.650 AC XY: 21674 AN XY: 33328

African (AFR) AF: 0.931 AC: 3219 AN: 3456

American (AMR) AF: 0.786 AC: 1727 AN: 2198

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 3249 AN: 4558

East Asian (EAS) AF: 0.793 AC: 7916 AN: 9988

South Asian (SAS) AF: 0.713 AC: 456 AN: 640

European-Finnish (FIN) AF: 0.625 AC: 35 AN: 56

Middle Eastern (MID) AF: 0.776 AC: 332 AN: 428

European-Non Finnish (NFE) AF: 0.582 AC: 25993 AN: 44648

Other (OTH) AF: 0.664 AC: 4036 AN: 6078

GnomAD4 genome AF: 0.707 AC: 107459 AN: 151942 Hom.: 39900 Cov.: 33 AF XY: 0.708 AC XY: 52586 AN XY: 74242

African (AFR) AF: 0.924 AC: 38393 AN: 41550

American (AMR) AF: 0.780 AC: 11909 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.715 AC: 2477 AN: 3462

East Asian (EAS) AF: 0.821 AC: 4244 AN: 5168

South Asian (SAS) AF: 0.749 AC: 3618 AN: 4828

European-Finnish (FIN) AF: 0.576 AC: 6077 AN: 10548

Middle Eastern (MID) AF: 0.825 AC: 241 AN: 292

European-Non Finnish (NFE) AF: 0.568 AC: 38520 AN: 67796

Other (OTH) AF: 0.720 AC: 1522 AN: 2114

Alfa AF: 0.611 Hom.: 132370

Bravo AF: 0.729

Asia WGS AF: 0.758 AC: 2629 AN: 3470

ClinVar

Significance: Likely pathogenic; protective

Submissions summary: Pathogenic:1 Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of breast Pathogenic:1

Jul 01, 2023

Institute of Biochemistry And Biotechnology, University of Veterinary and Animal Sciences, Lahore, Pakistan

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Three Vessel Coronary Disease Benign:1

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

Significance: protective

Review Status: no assertion criteria provided

Collection Method: clinical testing

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.38
DANN	Benign	0.63
PhyloP100		-2.2
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: rs1063192; hg19: chr9-22003367;