9-21971020-C-T

Variant names:

• chr9-21971020-C-T
• rs575031539
• NM_058195.4:c.382G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1 PM5 BP6 BS2

The NM_058195.4(CDKN2A):​c.382G>A​(p.Ala128Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,454,934 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A128L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CDKN2A NM_058195.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.0490
• Publications: 6 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 26 uncertain in NM_058195.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-21971019-GC-AG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9424.
• BP6: Variant 9-21971020-C-T is Benign according to our data. Variant chr9-21971020-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142725.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.382G>A	p.Ala128Thr	missense_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2
CDKN2A	NM_000077.5	c.339G>A	p.Leu113Leu	synonymous_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2	c.382G>A	p.Ala128Thr	missense_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1
CDKN2A	ENST00000304494.10	c.339G>A	p.Leu113Leu	synonymous_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 238240 AF XY: 0.00000766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000925

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1454934 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 724078

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5178

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111632

Other (OTH) AF: 0.00 AC: 0 AN: 60254

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000830 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

May 08, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

​The p.A128T variant (also known as c.382G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 382 of the p14 protein-encoding isoform. The alanine at codon 128 is replaced by threonine, an amino acid with similar properties. This alteration does not result in an amino acid change in the major, p16 transcript of CDKN2A. This alteration has been identified in one family with melanoma (FitzGerald MG et al. Proc. Natl. Acad. Sci. U.S.A., 1996 Aug;93:8541-5). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Nov 07, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Apr 04, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted CDKN2A c.382G>A at the cDNA level, p.Ala128Thr (A128T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC) in exon 2 of the p14-ARF protein. The CDKN2A gene encodes the p16 protein, and using an alternate reading frame, the p14-ARF protein as well. Of note, this variant also results in a change to the p16 protein; however, that amino acid substitution is silent (p.Leu113Leu). This variant was observed in individuals with personal and/or family histories of melanoma (FitzGerald 1996, Goldstein 2007). CDKN2A Ala128Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDKN2A Ala128Thr occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether CDKN2A Ala128Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Familial melanoma Benign:1

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	T;T
Eigen	Benign	0.076
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.48	.;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.50	D;D
MetaSVM	Benign	-0.47	T
PhyloP100		0.049
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.1	.;D
REVEL	Benign	0.29
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.39
MVP		0.95
ClinPred		0.34	T
GERP RS		1.6
PromoterAI		0.0059	Neutral
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs575031539; hg19: chr9-21971019;