9-21971180-G-T

Position:

• chr9-21971180-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000077.5(CDKN2A):​c.179C>A​(p.Ala60Glu) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A60V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.19

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a repeat ANK 2 (size 28) in uniprot entity CDN2A_HUMAN there are 15 pathogenic changes around while only 3 benign (83%) 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 chr9-21971180-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 9-21971180-G-T is Pathogenic according to our data. Variant chr9-21971180-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186239.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.179C>A	p.Ala60Glu	missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.222C>A	p.Gly74=	synonymous_variant	2/3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.179C>A	p.Ala60Glu	missense_variant	2/3	1	NM_000077.5	ENSP00000307101	P2
CDKN2A	ENST00000579755.2	c.222C>A	p.Gly74=	synonymous_variant	2/3	1	NM_058195.4	ENSP00000462950

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1444544 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718938

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2024

The p.A60E variant (also known as c.179C>A), located in coding exon 2 of the CDKN2A gene, results from a C to A substitution at nucleotide position 179. The alanine at codon 60 is replaced by glutamic acid, an amino acid with dissimilar properties. Other variants impacting this amino acid (p.A60R and p.A60V) have been reported in melanoma cohorts and are functionally deleterious (Levanat S et al. Croat Med J. 2003 Aug;44(4):418-24; Begg CB et al. J Natl Cancer Inst. 2005 Oct;97(20):1507-15; Berwick M et al. Cancer Epidemiol Biomarkers Prev. 2006 Aug;15(8):1520-5; Orlow I et al. J Invest Dermatol. 2007 May;127(5):1234-43; Kannengiesser C et al. Hum Mutat. 2009 Apr;30(4):564-74; McKenzie HA et al. Hum Mutat. 2010 Jun;31(6):692-701; Miller PJ et al. Hum Mutat. 2011 Aug;32(8):900-11; Maubec E et al. J Am Acad Dermatol. 2012 Dec;67(6):1257-64; Casula M et al. BMC Cancer. 2019 Aug;19(1):772). This amino acid change is expected to be destabilizing to the protein structure (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;T;.;.;.;.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.6	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.84
MutPred		0.63		Gain of disorder (P = 0.057);Gain of disorder (P = 0.057);.;Gain of disorder (P = 0.057);.;.;.;.;
MVP		0.99
MPC		1.3
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs36204594; hg19: chr9-21971179; COSMIC: COSV58692021; COSMIC: COSV58692021;