9-21993965-T-C

Variant names:

• chr9-21993965-T-C
• rs2811711
• NM_058195.4:c.193+174A>G

Variant summary

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

The NM_058195.4(CDKN2A):​c.193+174A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 720,858 control chromosomes in the GnomAD database, including 6,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1500 hom., cov: 31)
  • Exomes 𝑓: 0.12 (4785 hom.)
• Consequence: CDKN2A NM_058195.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.66

Genes affected

CDKN2A (HGNC:1787): (cyclin dependent kinase inhibitor 2A) This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]

LOC124902130 (HGNC:):

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=-0.79).
• BP6: Variant 9-21993965-T-C is Benign according to our data. Variant chr9-21993965-T-C is described in ClinVar as [Benign]. Clinvar id is 1246519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.193+174A>G		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2
CDKN2A	NM_001363763.2	c.-4+856A>G		intron_variant	Intron 1 of 2		NP_001350692.1
CDKN2A	XM_047422597.1	c.-4+582A>G		intron_variant	Intron 1 of 2		XP_047278553.1
LOC124902130	XR_007061436.1	n.64A>G		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2	c.193+174A>G		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20245 AN: 151924 Hom.: 1504 Cov.: 31

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0748

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.153

GnomAD4 exome AF: 0.122 AC: 69202 AN: 568816 Hom.: 4785 Cov.: 7 AF XY: 0.120 AC XY: 36100 AN XY: 301002

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.0841

Gnomad4 ASJ exome AF: 0.136

Gnomad4 EAS exome AF: 0.000406

Gnomad4 SAS exome AF: 0.0759

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.124

GnomAD4 genome AF: 0.133 AC: 20250 AN: 152042 Hom.: 1500 Cov.: 31 AF XY: 0.129 AC XY: 9570 AN XY: 74328

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.0744

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.153

Alfa AF: 0.113 Hom.: 356

Bravo AF: 0.138

Asia WGS AF: 0.0680 AC: 235 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.060
DANN	Benign	0.55

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: rs2811711; hg19: chr9-21993964;