chr9-21970917-C-T

Variant names:

• chr9-21970917-C-T
• rs3731249
• NM_000077.5:c.442G>A
• CDKN2A p.Ala148Thr

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_StrongB3_Supporting

The NM_000077.5(CDKN2A):c.442G>A (p.Ala148Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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). The variant allele was found at a cumulative frequency of 0.0244 (AC=39,384) in the gnomAD database across 1,612,214 control chromosomes, including 600 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0298. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). 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.A148V: Uncertain_significance (ClinVar VariationId 231700, 2 stars) The variant has been observed in cBioPortal in 4 samples across 4 studies and 2 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.). 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: 𝑓 0.020 (45 hom., cov: 32)
  • Exomes 𝑓: 0.025 (555 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:24 O:1
• Conservation: PhyloP100: 0.153
• Publications: 137 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: Likely_benign. The variant received -5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.0298 — exceeds 1% threshold (B1 applied)
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

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.442G>A p.Ala148Thr	missense	Exon 2 of 3	Prot: NP_000068.1 UniProt:
	CDKN2A NM_058195.4	MANE Plus Clinical	c.*86G>A	3_prime_UTR	Exon 2 of 3	Prot: NP_478102.2 UniProt:
	CDKN2A NM_001195132.2		c.442G>A p.Ala148Thr	missense	Exon 2 of 4	Prot: NP_001182061.1 UniProt:

CDKN2A NM_000077.5

MANE Select

HGVSc / HGVSpc.442G>Ap.Ala148Thr

Exon rankExon 2 of 3

missense

Prot: NP_000068.1UniProt: K7PML8P42771-1

CDKN2A NM_058195.4

MANE Plus Clinical

HGVSc / HGVSpc.*86G>A

Exon rankExon 2 of 3

3_prime_UTR

Prot: NP_478102.2UniProt: Q8N726-1

CDKN2A NM_001195132.2

HGVSc / HGVSpc.442G>Ap.Ala148Thr

Exon rankExon 2 of 4

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.442G>A p.Ala148Thr	missense	Exon 2 of 3	Prot: ENSP00000307101.5 UniProt:
	CDKN2A ENST00000498124.1	TSL:1	c.442G>A p.Ala148Thr	missense	Exon 2 of 4	Prot: ENSP00000418915.1 UniProt:
	CDKN2A ENST00000579755.2	TSL:1MANE Plus Clinical	c.*86G>A	3_prime_UTR	Exon 2 of 3	Prot: ENSP00000462950.1 UniProt:

CDKN2A ENST00000304494.10

TSL:1MANE Select

HGVSc / HGVSpc.442G>Ap.Ala148Thr

Exon rankExon 2 of 3

missense

Prot: ENSP00000307101.5UniProt: P42771-1

CDKN2A ENST00000498124.1

TSL:1

HGVSc / HGVSpc.442G>Ap.Ala148Thr

Exon rankExon 2 of 4

missense

Prot: ENSP00000418915.1UniProt: P42771-4

CDKN2A ENST00000579755.2

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.*86G>A

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0197	AC:2999	Hom:45	AN:152224	Cov:32
GnomAD2 exomes	AF: 0.0209	AC:5159	Hom:	AN:246916	Cov:
GnomAD4 exome	AF: 0.0249	AC:36385	Hom:555	AN:1459872	Cov:31
GnomAD4 genome	AF: 0.0197	AC:2999	Hom:45	AN:152342	Cov:32
TOPMed (Bravo)	AF: 0.0199	AC:5270	Hom:73	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0277	AC:19601	Hom:315	AN:706520	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0248	AC:58	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.000197	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0633	AC:19	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0225	AC:293	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.00462	AC:16	Hom:	AN:3476	Cov:
Qatari Genome	AF: 0.0201	AC:33	Hom:	AN:1642	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000410	AC:5	Hom:0	AN:122758	Cov:
Turkish Variome	AF: 0.0409	AC:266	Hom:14	AN:6496	Cov:
UK10K	AF: 0.0280	AC:212	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0358 *	398	11110	0.0376 *	662	17618
BipEx(Bipolar disorder (including schizoaffective))	0.0307	873	28420	0.0305	881	28844
Epi25(Epilepsy)	0.0253	1062	41958	0.0260	1736	66888
SCHEMA(Schizophrenia)	0.0171	2106	122928	0.0223	4315	193580

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (11)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	not provided (4)
-	-	3	Melanoma-pancreatic cancer syndrome (3)
-	-	1	Familial melanoma (1)
-	-	1	Li-Fraumeni syndrome;C2931038:Familial pancreatic carcinoma (1)
-	-	1	Melanoma, cutaneous malignant, susceptibility to, 2 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.2
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.16	N
FuncVEP CTI	Benign	0.089
GPN-Star LLR	N/A	-1.1
GPN-Star score	N/A	1.1
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	85/15	polymorphism (auto)
PhyloP100	Benign	0.15
popEVE	Benign	-3.0
PrimateAI	Benign	0.40	T
PromoterAI	N/A	0.0080	Neutral
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.27
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.041	D
Varity_R	N/A	0.096
VESM-3B	Benign	-3.4

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

dbSNP: rs3731249;

hg19: chr9-21970916;

COSMIC: COSV58682793;

COSMIC: COSV58682793;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar