rs1063192

Positions:

• chr9-22003368-G-A
• chr9-22003368-G-T

Variant summary

Our verdict is Benign. Variant got -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 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

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 -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 [protective]. Clinvar id is 812639.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, other=1}.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2B	NM_004936.4	c.*2619C>T		3_prime_UTR_variant	2/2	ENST00000276925.7	NP_004927.2
CDKN2B-AS1	NR_003529.3	n.371+8207G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2B	ENST00000276925.7	c.*2619C>T		3_prime_UTR_variant	2/2	1	NM_004936.4	ENSP00000276925	P1
CDKN2B-AS1	ENST00000650946.1	n.29+8207G>A		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.931

Gnomad4 AMR exome AF: 0.786

Gnomad4 ASJ exome AF: 0.713

Gnomad4 EAS exome AF: 0.793

Gnomad4 SAS exome AF: 0.713

Gnomad4 FIN exome AF: 0.625

Gnomad4 NFE exome AF: 0.582

Gnomad4 OTH exome AF: 0.664

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

Gnomad4 AFR AF: 0.924

Gnomad4 AMR AF: 0.780

Gnomad4 ASJ AF: 0.715

Gnomad4 EAS AF: 0.821

Gnomad4 SAS AF: 0.749

Gnomad4 FIN AF: 0.576

Gnomad4 NFE AF: 0.568

Gnomad4 OTH AF: 0.720

Alfa AF: 0.601 Hom.: 62955

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

Likely pathogenic, no assertion criteria provided

research

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

Jul 01, 2023

- -

Three Vessel Coronary Disease Benign:1

protective, no assertion criteria provided

clinical testing

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

-

- -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.38
DANN	Benign	0.63

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: rs1063192; hg19: chr9-22003367;