rs2811711

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-21993965-T-C
• chr9-21993965-T-A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058195.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.193+174A>G		intron	N/A	NP_478102.2	Q8N726-1
	CDKN2A	NM_001363763.2		c.-4+856A>G		intron	N/A	NP_001350692.1	P42771-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.193+174A>G		intron	N/A	ENSP00000462950.1	Q8N726-1
	CDKN2A	ENST00000494262.5	TSL:3	c.-87A>G		5_prime_UTR	Exon 2 of 4	ENSP00000464952.1	P42771-2
	CDKN2A	ENST00000530628.2	TSL:5	c.193+174A>G		intron	N/A	ENSP00000432664.2	Q8N726-1

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

African (AFR) AF: 0.163 AC: 2583 AN: 15850

American (AMR) AF: 0.0841 AC: 2636 AN: 31348

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 2339 AN: 17248

East Asian (EAS) AF: 0.000406 AC: 13 AN: 31992

South Asian (SAS) AF: 0.0759 AC: 4239 AN: 55862

European-Finnish (FIN) AF: 0.102 AC: 3257 AN: 31810

Middle Eastern (MID) AF: 0.115 AC: 275 AN: 2388

European-Non Finnish (NFE) AF: 0.142 AC: 50084 AN: 351760

Other (OTH) AF: 0.124 AC: 3776 AN: 30558

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

African (AFR) AF: 0.158 AC: 6565 AN: 41424

American (AMR) AF: 0.111 AC: 1700 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 492 AN: 3468

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5170

South Asian (SAS) AF: 0.0744 AC: 359 AN: 4824

European-Finnish (FIN) AF: 0.100 AC: 1064 AN: 10594

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9431 AN: 67960

Other (OTH) AF: 0.153 AC: 323 AN: 2110

Alfa AF: 0.120 Hom.: 484

Bravo AF: 0.138

Asia WGS AF: 0.0680 AC: 235 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.060
DANN	Benign	0.55
PhyloP100		-2.7
PromoterAI		0.039	Neutral
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: rs2811711; hg19: chr9-21993964;