9-21970902-C-G

Position:

• chr9-21970902-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000077.5(CDKN2A):​c.457G>C​(p.Asp153His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D153Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.07

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Cyclin-dependent kinase inhibitor 2A (size 155) in uniprot entity CDN2A_HUMAN there are 42 pathogenic changes around while only 12 benign (78%) 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 chr9-21970902-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.457G>C	p.Asp153His	missense_variant, splice_region_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.*101G>C		splice_region_variant	2/3	ENST00000579755.2	NP_478102.2
CDKN2A	NM_058195.4	c.*101G>C		3_prime_UTR_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.457G>C	p.Asp153His	missense_variant, splice_region_variant	2/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.*101G>C		splice_region_variant	2/3	1	NM_058195.4	ENSP00000462950.1
CDKN2A	ENST00000579755	c.*101G>C		3_prime_UTR_variant	2/3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2021

The p.D153H variant (also known as c.457G>C), located in coding exon 2 of the CDKN2A gene, results from a G to C substitution at nucleotide position 457. The amino acid change results in aspartic acid to histidine at codon 153, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is well conserved on limited sequence alignment. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Another alteration impacting the same donor site (p.D153Y, c.457G>T) has been described in the literature in individuals with CDKN2A-related disease (Moskaluk CA et al. Hum. Mutat. 1998;12(1):70; Lynch HT et al. Cancer. 2002 Jan;94(1):84-96; Rutter JL et al. Oncogene. 2003 Jul; 22(28):4444-8; Demenais F et al. J. Natl. Cancer Inst. 2010 Oct 20;102(20):1568-83; Lucas AL et al. Cancer. 2014 Jul;120(13):1960-7; Zhen DB et al. Genet. Med. 2015 Jul;17(7):569-77), and RT-PCR analysis for c.457G>T has shown aberrant splicing (Rutter JL et al. Oncogene. 2003 Jul; 22(28):4444-8; Loo JC et al. Oncogene. 2003 Sep;22(41):6387-94). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 13, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 153 of the CDKN2A (p16INK4a) protein (p.Asp153His). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with exocrine pancreatic neoplasm (PMID: 29506128). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Benign	0.099
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.40	T;.;.;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.56	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.73	N;.;.;.
REVEL	Uncertain	0.45
Sift	Benign	0.077	T;.;.;.
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.67	P;.;.;.
Vest4		0.20
MutPred		0.37		Loss of phosphorylation at S152 (P = 0.1298);.;.;.;
MVP		0.96
ClinPred		0.32	T
GERP RS		3.3
Varity_R		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.76		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-21970901; COSMIC: COSV105891330; COSMIC: COSV105891330;