chr9-21974679-T-G

Position:

• chr9-21974679-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.149A>C​(p.Gln50Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense, splice_region
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.65

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]

ENSG00000264545 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a turn (size 2) in uniprot entity CDN2A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 9-21974679-T-G is Pathogenic according to our data. Variant chr9-21974679-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 187713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.149A>C	p.Gln50Pro	missense_variant, splice_region_variant	1/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-3471A>C		intron_variant		ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.149A>C	p.Gln50Pro	missense_variant, splice_region_variant	1/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.194-3471A>C		intron_variant		1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2024

The p.Q50P variant (also known as c.149A>C), located in coding exon 1 of the CDKN2A gene, results from an A to C substitution at nucleotide position 149. The glutamine at codon 50 is replaced by proline, an amino acid with similar properties. This alteration was initially reported in a melanoma and pancreatic cancer kindred. The proband was diagnosed with melanoma at age 29y and had three first-degree relatives (FDRs) with melanoma as well as one FDR and one second-degree relative (SDR) with pancreatic cancer (Lynch HT, Cancer 2002 Jan; 94(1):84-96). This alteration has also been reported in a proband with melanoma who had a family history of melanoma in 2/7 FDRs (Begg CB, J. Natl. Cancer Inst. 2005 Oct; 97(20):1507-15). RT-PCR of RNA extracted from lymphoblastoid cells showed an incomplete splicing impact for this alteration, predicted to result in a protein with an in-frame deletion of 23 amino acids (Loo JC, Oncogene 2003 Sep; 22(41):6387-94). In addition, a yeast-based assay reported that this alteration impaired binding with CDK4 (Loo JC, Oncogene 2003 Sep; 22(41):6387-94). Another alteration at the same codon, p.Q50R (c.149A>G), has been detected in melanoma and pancreatic cancer cohorts and was reported to segregate with melanoma in at least six melanoma-affected individuals in one family (Walker GJ et al. Hum. Mol. Genet. 1995 Oct;4:1845-52; Box NF et al. Am. J. Hum. Genet. 2001 Oct;69:765-73). This amino acid position is highly conserved in available vertebrate species. In addition, this missense 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. -

Familial melanoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2023

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 50 of the CDKN2A (p16INK4a) protein (p.Gln50Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma (PMID: 11815963, 16234564, 16896043, 30967399). ClinVar contains an entry for this variant (Variation ID: 187713). 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. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 14508519). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 14508519). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.20	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.2	D;.;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.86
MutPred		0.67		Loss of MoRF binding (P = 0.0317);Loss of MoRF binding (P = 0.0317);Loss of MoRF binding (P = 0.0317);
MVP		0.99
MPC		1.3
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.88
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs587778189; hg19: chr9-21974678; COSMIC: COSV105891294; COSMIC: COSV105891294;