rs971657556

Variant names:

• chr9-21970976-C-G
• rs971657556
• NM_000077.5:c.383G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-21970976-C-G
• chr9-21970976-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000077.5(CDKN2A):​c.383G>C​(p.Arg128Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,694 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R128Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.70
• Publications: 15 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 43 uncertain in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.383G>C	p.Arg128Pro	missense_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.*27G>C		3_prime_UTR_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.383G>C	p.Arg128Pro	missense_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.*27G>C		3_prime_UTR_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458694 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725804

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60306

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R128P variant (also known as c.383G>C), located in coding exon 2 of the CDKN2A gene, results from a G to C substitution at nucleotide position 383. The arginine at codon 128 is replaced by proline, an amino acid with dissimilar properties. Of note, this variant is also known as c.*27G>C in the p14(ARF) isoform. A functional study reported this variant as deleterious based on in-vitro assessment of impact on proliferation in human pancreatic cancer cell lines (Kimura H et al. Elife, 2022 Jan;11:). This variant was identified as germline in a patient with high grade epithelioid leiomyosarcoma although loss of heterozygosity (LOH) was not detected in the tumor (Carvalho NA et al. J Med Genet, 2023 Dec;61:61-68). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Familial melanoma Uncertain:1

Nov 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 128 of the CDKN2A (p16INK4a) protein (p.Arg128Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. ClinVar contains an entry for this variant (Variation ID: 483344). 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 tolerated. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 35001868). 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	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T;T;.;.;.;.;T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.29	T;T;.;T;.;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
PhyloP100		-1.7
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N;.;.;N;.;.;.;.
REVEL	Pathogenic	0.66
Sift	Benign	0.12	T;.;.;T;.;.;.;.
Sift4G	Benign	0.20	T;T;T;T;T;T;T;T
Polyphen		0.78	P;.;.;.;.;.;.;.
Vest4		0.42
MutPred		0.47		Loss of MoRF binding (P = 0.002);Loss of MoRF binding (P = 0.002);.;Loss of MoRF binding (P = 0.002);.;.;.;.;
MVP		0.98
MPC		0.99
ClinPred		0.32	T
GERP RS		-3.3
PromoterAI		0.0034	Neutral
Varity_R		0.76
gMVP		0.85
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs971657556; hg19: chr9-21970975;