9-22006274-G-T

Position:

• chr9-22006274-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004936.4(CDKN2B):​c.157-27C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0853 in 1,600,488 control chromosomes in the GnomAD database, including 6,023 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (573 hom., cov: 33)
  • Exomes 𝑓: 0.085 (5450 hom.)
• Consequence: CDKN2B NM_004936.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0560

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-22006274-G-T is Benign according to our data. Variant chr9-22006274-G-T is described in ClinVar as [Benign]. Clinvar id is 1279271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2B	NM_004936.4	c.157-27C>A		intron_variant		ENST00000276925.7
CDKN2B-AS1	NR_003529.3	n.371+11113G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2B	ENST00000276925.7	c.157-27C>A		intron_variant		1	NM_004936.4	P1
CDKN2B-AS1	ENST00000650946.1	n.29+11113G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0866 AC: 13187 AN: 152238 Hom.: 571 Cov.: 33

Gnomad AFR AF: 0.0957

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0742

Gnomad ASJ AF: 0.0959

Gnomad EAS AF: 0.0188

Gnomad SAS AF: 0.0461

Gnomad FIN AF: 0.0815

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0929

Gnomad OTH AF: 0.0879

GnomAD3 exomes AF: 0.0745 AC: 16944 AN: 227284 Hom.: 737 AF XY: 0.0758 AC XY: 9541 AN XY: 125952

Gnomad AFR exome AF: 0.0941

Gnomad AMR exome AF: 0.0483

Gnomad ASJ exome AF: 0.0981

Gnomad EAS exome AF: 0.0208

Gnomad SAS exome AF: 0.0549

Gnomad FIN exome AF: 0.0791

Gnomad NFE exome AF: 0.0926

Gnomad OTH exome AF: 0.0801

GnomAD4 exome AF: 0.0852 AC: 123324 AN: 1448132 Hom.: 5450 Cov.: 32 AF XY: 0.0848 AC XY: 61154 AN XY: 720918

Gnomad4 AFR exome AF: 0.0973

Gnomad4 AMR exome AF: 0.0512

Gnomad4 ASJ exome AF: 0.0941

Gnomad4 EAS exome AF: 0.0175

Gnomad4 SAS exome AF: 0.0561

Gnomad4 FIN exome AF: 0.0763

Gnomad4 NFE exome AF: 0.0908

Gnomad4 OTH exome AF: 0.0872

GnomAD4 genome AF: 0.0867 AC: 13209 AN: 152356 Hom.: 573 Cov.: 33 AF XY: 0.0854 AC XY: 6364 AN XY: 74502

Gnomad4 AFR AF: 0.0960

Gnomad4 AMR AF: 0.0741

Gnomad4 ASJ AF: 0.0959

Gnomad4 EAS AF: 0.0193

Gnomad4 SAS AF: 0.0464

Gnomad4 FIN AF: 0.0815

Gnomad4 NFE AF: 0.0928

Gnomad4 OTH AF: 0.0870

Alfa AF: 0.0885 Hom.: 218

Bravo AF: 0.0850

Asia WGS AF: 0.0440 AC: 153 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.1
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2069426; hg19: chr9-22006273; COSMIC: COSV99439453; COSMIC: COSV99439453;