chr9-21974685-G-C

Variant names:

• chr9-21974685-G-C
• rs763804037
• NM_000077.5:c.143C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000077.5(CDKN2A):​c.143C>G​(p.Pro48Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P48L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 6.09
• 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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), 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:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 50 uncertain in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-21974685-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2625888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 9-21974685-G-C is Pathogenic according to our data. Variant chr9-21974685-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 231262.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	NM_000077.5	MANE Select	c.143C>G	p.Pro48Arg	missense	Exon 1 of 3	NP_000068.1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.194-3477C>G		intron	N/A	NP_478102.2
	CDKN2A	NM_001195132.2		c.143C>G	p.Pro48Arg	missense	Exon 1 of 4	NP_001182061.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.143C>G	p.Pro48Arg	missense	Exon 1 of 3	ENSP00000307101.5
	CDKN2A	ENST00000498124.1	TSL:1	c.143C>G	p.Pro48Arg	missense	Exon 1 of 4	ENSP00000418915.1
	CDKN2A	ENST00000380151.3	TSL:1	n.143C>G		non_coding_transcript_exon	Exon 1 of 3	ENSP00000369496.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 31, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P48R variant (also known as c.143C>G), located in coding exon 1 of the CDKN2A gene, results from a C to G substitution at nucleotide position 143. The proline at codon 48 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been observed in multiple individuals with a personal and/or family history of pancreatic cancer (Ambry internal data; Debniak T et al. Eur J Cancer Prev, 2008 Oct;17:389-91; Lowery MA et al. J Natl Cancer Inst, 2018 Oct;110:1067-1074). Based on internal structural analysis, P48R is more disruptive to the structure of CDKN2A than nearby internally pathogenic variants, including p.P48T at the same position (Russo, AA et al. Nature 1998 Sep;395(6699):237-43; Byeon IJ et al. Mol Cell 1998 Feb;1(3):421-31). The p.P48T alteration has been observed in affected individuals and reported to have a deleterious impact in protein functional studies (Moore PS et al. Hum Mutat, 2000 Nov;16:447-8; Della Torre G et al. Br J Cancer, 2001 Sep;85:836-44; Miller PJ et al. Hum Mutat, 2011 Aug;32:900-11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Melanoma-pancreatic cancer syndrome Uncertain:1

Apr 21, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

Familial melanoma Uncertain:1

Jun 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 48 of the CDKN2A (p16INK4a) protein (p.Pro48Arg). This variant is present in population databases (rs763804037, gnomAD 0.006%). This missense change has been observed in individual(s) with pancreatic cancer or melanoma (PMID: 18714178, 21462282, 28873162, 29506128). ClinVar contains an entry for this variant (Variation ID: 231262). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Pro48 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11058911, 11556834, 17625456, 28830827). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.97	D
PhyloP100		6.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.78		Gain of MoRF binding (P = 0.0134)
MVP		1.0
MPC		1.3
ClinPred		0.98	D
GERP RS		4.9
PromoterAI		-0.15	Neutral
Varity_R		0.69
gMVP		0.98
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs763804037; hg19: chr9-21974684; COSMIC: COSV58688196; COSMIC: COSV58688196;