NM_000077.5:c.335_337dupGTC

Variant names:

• chr9-21971021-A-AGAC
• rs768966657
• NM_000077.5:c.335_337dupGTC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 17P and 1B. PS3 PM1 PM2 PM4_Supporting PP5_Very_Strong BS2_Supporting

The NM_000077.5(CDKN2A):​c.335_337dupGTC​(p.Arg112dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.00000344 in 1,455,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000212850: This alteration is located in the functionally-important ankyrin repeat region and has been shown to result in loss of binding capacity for cdk4 and cdk6 in vitro (Ruas M, et al. Oncogene 1999 Sep" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L113L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CDKN2A NM_000077.5 conservative_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.00
• Publications: 13 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000212850: This alteration is located in the functionally-important ankyrin repeat region and has been shown to result in loss of binding capacity for cdk4 and cdk6 in vitro (Ruas M, et al. Oncogene 1999 Sep; 18(39):5423-34; Borg A, J. Natl. Cancer Inst. 2000 Aug; 92(15):1260-6).; SCV001349019: Functional studies have shown that this variant impairs the binding to CDK4 and CDK6 in vitro (PMID: 10498896, 10922411).; SCV000283443: Experimental studies have shown that this variant affects CDKN2A (p16INK4a) function (PMID: 10922411).; SCV000292539: Published functional studies demonstrate a damaging effect: inability to bind CDK4 and CDK6 (Ruas et al., 1999; Borg et al., 2000)
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 48 uncertain in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000077.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 9-21971021-A-AGAC is Pathogenic according to our data. Variant chr9-21971021-A-AGAC is described in ClinVar as Pathogenic. ClinVar VariationId is 183759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.335_337dupGTC	p.Arg112dup	conservative_inframe_insertion	Exon 2 of 3	NP_000068.1	P42771-1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.378_380dupGTC	p.Ser127dup	disruptive_inframe_insertion	Exon 2 of 3	NP_478102.2	Q8N726-1
	CDKN2A	NM_001195132.2		c.335_337dupGTC	p.Arg112dup	conservative_inframe_insertion	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.335_337dupGTC	p.Arg112dup	conservative_inframe_insertion	Exon 2 of 3	ENSP00000307101.5	P42771-1
	CDKN2A	ENST00000498124.1	TSL:1	c.335_337dupGTC	p.Arg112dup	conservative_inframe_insertion	Exon 2 of 4	ENSP00000418915.1	P42771-4
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.378_380dupGTC	p.Ser127dup	disruptive_inframe_insertion	Exon 2 of 3	ENSP00000462950.1	Q8N726-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000126 AC: 3 AN: 238418 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000277

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1455010 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724106

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5198

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111638

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Familial melanoma (1)
1	-	-	Melanoma and neural system tumor syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs768966657; hg19: chr9-21971020;