rs730881674

Variant names:

• chr9-21971115-CGGGTCGGGTGAGAGTGGCG-C
• rs730881674
• NM_000077.5:c.225_243delCGCCACTCTCACCCGACCC

Your query was ambiguous. Multiple possible variants found:

• chr9-21971115-CGGGTCGGGTGAGAGTGGCG-C
• chr9-21971115-CGGGTCGGGTGAGAGTGGCG-CGGGTCGGGTGAGAGTGGCGGGGTCGGGTGAGAGTGGCG

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.225_243delCGCCACTCTCACCCGACCC​(p.Ala76CysfsTer64) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000689 in 1,451,914 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000210937: Published functional studies demonstrate a damaging effect: loss of CDK4/CDK6 binding, loss of cell cycle inhibitory activity, and altered subcellular localization (McKenzie 2010)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P75P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDKN2A NM_000077.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 5.60
• Publications: 38 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]

CDKN2A Gene-Disease associations (from GenCC):

• melanoma, cutaneous malignant, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• melanoma-pancreatic cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• familial atypical multiple mole melanoma syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma and neural system tumor syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000210937: Published functional studies demonstrate a damaging effect: loss of CDK4/CDK6 binding, loss of cell cycle inhibitory activity, and altered subcellular localization (McKenzie 2010);; SCV000211931: Experimental studies have shown that this premature translational stop signal affects CDKN2A (p16INK4a) function (PMID: 20340136).; SCV000581507: Functional analysis of this alteration revealed that transfected cells show altered subcellular localization, and significantly reduced binding affinity to CDK4 relative to wild type cells (McKenzie HA et al. Hum. Mutat. 2010 Jun;31:692-701).
• PP5: Variant 9-21971115-CGGGTCGGGTGAGAGTGGCG-C is Pathogenic according to our data. Variant chr9-21971115-CGGGTCGGGTGAGAGTGGCG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 182411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000077.5. 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_000077.5	MANE Select	c.225_243delCGCCACTCTCACCCGACCC	p.Ala76CysfsTer64	frameshift	Exon 2 of 3	NP_000068.1	P42771-1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.268_286delCGCCACTCTCACCCGACCC	p.Arg90ValfsTer76	frameshift	Exon 2 of 3	NP_478102.2	Q8N726-1
	CDKN2A	NM_001195132.2		c.225_243delCGCCACTCTCACCCGACCC	p.Ala76CysfsTer64	frameshift	Exon 2 of 4	NP_001182061.1	P42771-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.225_243delCGCCACTCTCACCCGACCC	p.Ala76CysfsTer64	frameshift	Exon 2 of 3	ENSP00000307101.5	P42771-1
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.268_286delCGCCACTCTCACCCGACCC	p.Arg90ValfsTer76	frameshift	Exon 2 of 3	ENSP00000462950.1	Q8N726-1
	CDKN2A	ENST00000498124.1	TSL:1	c.225_243delCGCCACTCTCACCCGACCC	p.Ala76CysfsTer64	frameshift	Exon 2 of 4	ENSP00000418915.1	P42771-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451914 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 722684

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5470

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111496

Other (OTH) AF: 0.00 AC: 0 AN: 60256

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	Melanoma-pancreatic cancer syndrome (2)
1	-	-	CDKN2A-related disorder (1)
1	-	-	Familial melanoma (1)
1	-	-	Familial pancreatic carcinoma (1)
1	-	-	Melanoma and neural system tumor syndrome (1)
1	-	-	not provided (1)
-	-	-	Melanoma and neural system tumor syndrome;C1838547:Melanoma-pancreatic cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730881674; hg19: chr9-21971114; COSMIC: COSV58696968; COSMIC: COSV58696968;