chr9-21971149-G-A

Variant names:

• chr9-21971149-G-A
• rs864622570
• NM_058195.4:c.253C>T
• CDKN2A p.Gln85*

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 9 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2BP6

The NM_058195.4(CDKN2A):c.253C>T (p.Gln85*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.0000131 (AC=2) in the gnomAD database across 152,132 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000488. In-silico predictor (BayesDel (noAF)) 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 (no review 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: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: CDKN2A NM_058195.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.958
• Publications: 2 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 2 of 3) at amino acid 85 of 132, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000488 — very rare for AD/XL gene (base 0.0001, raised to 0.00011 by highest known P/LP ClinVar AF 0.00011) — PM2 moderate.
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_058195.4. 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_058195.4	MANE Plus Clinical	c.253C>T p.Gln85*	stop_gained	Exon 2 of 3	Prot: NP_478102.2 UniProt:
	CDKN2A NM_000077.5	MANE Select	c.210C>T p.Pro70Pro	synonymous	Exon 2 of 3	Prot: NP_000068.1 UniProt:
	CDKN2A NM_001195132.2		c.210C>T p.Pro70Pro	synonymous	Exon 2 of 4	Prot: NP_001182061.1 UniProt:

CDKN2A NM_058195.4

MANE Plus Clinical

HGVSc / HGVSpc.253C>Tp.Gln85*

Exon rankExon 2 of 3

stop_gained

Prot: NP_478102.2UniProt: Q8N726-1

CDKN2A NM_000077.5

MANE Select

HGVSc / HGVSpc.210C>Tp.Pro70Pro

Exon rankExon 2 of 3

synonymous

Prot: NP_000068.1UniProt: K7PML8P42771-1

CDKN2A NM_001195132.2

HGVSc / HGVSpc.210C>Tp.Pro70Pro

Exon rankExon 2 of 4

synonymous

Prot: NP_001182061.1UniProt: P42771-4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CDKN2A ENST00000579755.2	TSL:1MANE Plus Clinical	c.253C>T p.Gln85*	stop_gained	Exon 2 of 3	Prot: ENSP00000462950.1 UniProt:
	CDKN2A ENST00000304494.10	TSL:1MANE Select	c.210C>T p.Pro70Pro	synonymous	Exon 2 of 3	Prot: ENSP00000307101.5 UniProt:
	CDKN2A ENST00000498124.1	TSL:1	c.210C>T p.Pro70Pro	synonymous	Exon 2 of 4	Prot: ENSP00000418915.1 UniProt:

CDKN2A ENST00000579755.2

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.253C>Tp.Gln85*

Exon rankExon 2 of 3

stop_gained

Prot: ENSP00000462950.1UniProt: Q8N726-1

CDKN2A ENST00000304494.10

TSL:1MANE Select

HGVSc / HGVSpc.210C>Tp.Pro70Pro

Exon rankExon 2 of 3

synonymous

Prot: ENSP00000307101.5UniProt: P42771-1

CDKN2A ENST00000498124.1

TSL:1

HGVSc / HGVSpc.210C>Tp.Pro70Pro

Exon rankExon 2 of 4

synonymous

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152132	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152132	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16840	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	-	1	Familial melanoma (1)
-	1	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	17
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Uncertain	1.0
Eigen	Benign	0.17
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.90	D
GPN-Star LLR	N/A	-2.7
GPN-Star score	N/A	2.7
Mutation Taster	N/A	0/200	disease causing (fs/PTC)
PhyloP100	Benign	0.96
PromoterAI	N/A	-0.018	Neutral

Showing 13 of 13 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	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: rs864622570;

hg19: chr9-21971148;

COSMIC: COSV58725664;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar