chr9-21970915-CGC-TGT

Variant names:

• chr9-21970915-CGC-TGT
• NM_000077.5:c.442_444delGCGinsACA
• CDKN2A p.Ala148Thr

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateB2_Supporting

The NM_000077.5(CDKN2A):c.442_444delGCGinsACA (p.Ala148Thr) variant causes a missense change. The gene CDKN2A is a tumor suppressor gene (CancerMine: 433 TSG, 144 oncogene, 88 driver citations). The gene CDKN2A is a known oncogene (CancerMine: 433 TSG, 144 oncogene, 88 driver citations). The gene CDKN2A is a cancer driver gene (CancerMine: 433 TSG, 144 oncogene, 88 driver citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.A148= (synonymous): Likely_benign (ClinVar VariationId 921245, 2 stars); p.A148= (synonymous): Likely_benign (ClinVar VariationId 923208, 2 stars); p.A148P: Uncertain_significance (ClinVar VariationId 483343, 2 stars); p.A148S: Uncertain_significance (ClinVar VariationId 406706, 2 stars); p.A148T: Benign (ClinVar VariationId 41580, 2 stars); p.A148V: Uncertain_significance (ClinVar VariationId 231700, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.153
• Publications: 0 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, Genomics England PanelApp, Ambry Genetics
• 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:):

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	B2Does not fit gene mode of action		Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context); Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000077.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CDKN2A NM_000077.5	MANE Select	c.442_444delGCGinsACA p.Ala148Thr	missense	N/A	Prot: NP_000068.1 UniProt:
	CDKN2A NM_058195.4	MANE Plus Clinical	c.*86_*88delGCGinsACA	3_prime_UTR	Exon 2 of 3	Prot: NP_478102.2 UniProt:
	CDKN2A NM_001195132.2		c.442_444delGCGinsACA p.Ala148Thr	missense	N/A	Prot: NP_001182061.1 UniProt:

CDKN2A NM_000077.5

MANE Select

HGVSc / HGVSpc.442_444delGCGinsACAp.Ala148Thr

Exon rankN/A

missense

Prot: NP_000068.1UniProt: K7PML8P42771-1

CDKN2A NM_058195.4

MANE Plus Clinical

HGVSc / HGVSpc.*86_*88delGCGinsACA

Exon rankExon 2 of 3

3_prime_UTR

Prot: NP_478102.2UniProt: Q8N726-1

CDKN2A NM_001195132.2

HGVSc / HGVSpc.442_444delGCGinsACAp.Ala148Thr

Exon rankN/A

missense

Prot: NP_001182061.1UniProt: P42771-4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CDKN2A ENST00000304494.10	TSL:1MANE Select	c.442_444delGCGinsACA p.Ala148Thr	missense	N/A	Prot: ENSP00000307101.5 UniProt:
	CDKN2A ENST00000498124.1	TSL:1	c.442_444delGCGinsACA p.Ala148Thr	missense	N/A	Prot: ENSP00000418915.1 UniProt:
	CDKN2A ENST00000579755.2	TSL:1MANE Plus Clinical	c.*86_*88delGCGinsACA	3_prime_UTR	Exon 2 of 3	Prot: ENSP00000462950.1 UniProt:

CDKN2A ENST00000304494.10

TSL:1MANE Select

HGVSc / HGVSpc.442_444delGCGinsACAp.Ala148Thr

Exon rankN/A

missense

Prot: ENSP00000307101.5UniProt: P42771-1

CDKN2A ENST00000498124.1

TSL:1

HGVSc / HGVSpc.442_444delGCGinsACAp.Ala148Thr

Exon rankN/A

missense

Prot: ENSP00000418915.1UniProt: P42771-4

CDKN2A ENST00000579755.2

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.*86_*88delGCGinsACA

Exon rankExon 2 of 3

3_prime_UTR

Prot: ENSP00000462950.1UniProt: Q8N726-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	0.15

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr9-21970914;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar