9-22006349-C-T

Position:

• chr9-22006349-C-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.157-102G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,496,034 control chromosomes in the GnomAD database, including 9,842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1880 hom., cov: 33)
  • Exomes 𝑓: 0.10 (7962 hom.)
• Consequence: CDKN2B NM_004936.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.31

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=-0.91).
• BP6: Variant 9-22006349-C-T is Benign according to our data. Variant chr9-22006349-C-T is described in ClinVar as [Benign]. Clinvar id is 812646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2B	NM_004936.4	c.157-102G>A		intron_variant		ENST00000276925.7
CDKN2B-AS1	NR_003529.3	n.371+11188C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2B	ENST00000276925.7	c.157-102G>A		intron_variant		1	NM_004936.4	P1
CDKN2B-AS1	ENST00000650946.1	n.29+11188C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21684 AN: 152114 Hom.: 1869 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0988

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0835

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.0998

Gnomad OTH AF: 0.136

GnomAD4 exome AF: 0.103 AC: 138758 AN: 1343802 Hom.: 7962 AF XY: 0.104 AC XY: 69235 AN XY: 668514

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.0676

Gnomad4 ASJ exome AF: 0.107

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.0785

Gnomad4 NFE exome AF: 0.0953

Gnomad4 OTH exome AF: 0.114

GnomAD4 genome AF: 0.143 AC: 21732 AN: 152232 Hom.: 1880 Cov.: 33 AF XY: 0.142 AC XY: 10558 AN XY: 74458

Gnomad4 AFR AF: 0.244

Gnomad4 AMR AF: 0.0987

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.217

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.0835

Gnomad4 NFE AF: 0.0998

Gnomad4 OTH AF: 0.136

Alfa AF: 0.112 Hom.: 328

Bravo AF: 0.147

Asia WGS AF: 0.148 AC: 514 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	- -

Three Vessel Coronary Disease Benign:1

Benign, no assertion criteria provided

clinical testing

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.049
DANN	Benign	0.41

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: rs974336; hg19: chr9-22006348;