chr9-21971147-TTG-CTT

Variant names:

• chr9-21971147-TTG-CTT
• NM_000077.5:c.210_212delCAAinsAAG

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO7_Supporting

The NM_000077.5(CDKN2A):c.210_212delCAAinsAAG (p.Asn71Ser) 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. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.41). 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.Q85*: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 220535); p.Q85H: Uncertain_significance (ClinVar VariationId 1786361, 2 stars); p.Q85L: Uncertain_significance (ClinVar VariationId 485514, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41
• 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 3 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])
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 11 pathogenic, 1 benign (OR vs. background: 38.3); Variant does not impact splicing — splice-hotspot path not applicable

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.210_212delCAAinsAAG p.Asn71Ser	missense	N/A	Prot: NP_000068.1 UniProt:
	CDKN2A NM_058195.4	MANE Plus Clinical	c.253_255delCAAinsAAG p.Gln85Lys	missense	N/A	Prot: NP_478102.2 UniProt:
	CDKN2A NM_001195132.2		c.210_212delCAAinsAAG p.Asn71Ser	missense	N/A	Prot: NP_001182061.1 UniProt:

CDKN2A NM_000077.5

MANE Select

HGVSc / HGVSpc.210_212delCAAinsAAGp.Asn71Ser

Exon rankN/A

missense

Prot: NP_000068.1UniProt: K7PML8P42771-1

CDKN2A NM_058195.4

MANE Plus Clinical

HGVSc / HGVSpc.253_255delCAAinsAAGp.Gln85Lys

Exon rankN/A

missense

Prot: NP_478102.2UniProt: Q8N726-1

CDKN2A NM_001195132.2

HGVSc / HGVSpc.210_212delCAAinsAAGp.Asn71Ser

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.210_212delCAAinsAAG p.Asn71Ser	missense	N/A	Prot: ENSP00000307101.5 UniProt:
	CDKN2A ENST00000579755.2	TSL:1MANE Plus Clinical	c.253_255delCAAinsAAG p.Gln85Lys	missense	N/A	Prot: ENSP00000462950.1 UniProt:
	CDKN2A ENST00000498124.1	TSL:1	c.210_212delCAAinsAAG p.Asn71Ser	missense	N/A	Prot: ENSP00000418915.1 UniProt:

CDKN2A ENST00000304494.10

TSL:1MANE Select

HGVSc / HGVSpc.210_212delCAAinsAAGp.Asn71Ser

Exon rankN/A

missense

Prot: ENSP00000307101.5UniProt: P42771-1

CDKN2A ENST00000579755.2

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.253_255delCAAinsAAGp.Gln85Lys

Exon rankN/A

missense

Prot: ENSP00000462950.1UniProt: Q8N726-1

CDKN2A ENST00000498124.1

TSL:1

HGVSc / HGVSpc.210_212delCAAinsAAGp.Asn71Ser

Exon rankN/A

missense

Prot: ENSP00000418915.1UniProt: P42771-4

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

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	7.4

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: chr9-21971146;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar