chr9-21974745-A-C

Variant names:

• chr9-21974745-A-C
• rs775176191
• NM_000077.5:c.83T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 5P and 3B. PM1 PM2 PP3 BP4_Moderate BP6

The NM_000077.5(CDKN2A):​c.83T>G​(p.Val28Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. V28M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.42
• Publications: 8 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 2 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 44 uncertain in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.19393542).
• BP6: Variant 9-21974745-A-C is Benign according to our data. Variant chr9-21974745-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 236991.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000077.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	NM_000077.5	MANE Select	c.83T>G	p.Val28Gly	missense	Exon 1 of 3	NP_000068.1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.194-3537T>G		intron	N/A	NP_478102.2
	CDKN2A	NM_001195132.2		c.83T>G	p.Val28Gly	missense	Exon 1 of 4	NP_001182061.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.83T>G	p.Val28Gly	missense	Exon 1 of 3	ENSP00000307101.5
	CDKN2A	ENST00000498124.1	TSL:1	c.83T>G	p.Val28Gly	missense	Exon 1 of 4	ENSP00000418915.1
	CDKN2A	ENST00000380151.3	TSL:1	n.83T>G		non_coding_transcript_exon	Exon 1 of 3	ENSP00000369496.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000419 AC: 1 AN: 238664 AF XY: 0.00000763

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: 0.0000517

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.000600 AC: 72

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Sep 17, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with glycine at codon 28 of the CDKN2A (p16INK4A) protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ≥0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in a family affected with two cases of melanoma (PMID: 12001124). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Jun 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V28G variant (also known as c.83T>G), located in coding exon 1 of the CDKN2A gene, results from a T to G substitution at nucleotide position 83. The valine at codon 28 is replaced by glycine, an amino acid with dissimilar properties. This alteration was identified in individuals with multiple primary melanomas (Blackwood MA et al. Cancer, 2002 Apr;94:2248-55; 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. Based on the available evidence, the clinical significance of this variant remains unclear.

not provided Uncertain:1

May 02, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with multiple primary melanoma (Blackwood et al., 2002); This variant is associated with the following publications: (PMID: 16173922, 9653180, 9529249, 12001124, 33076392, 12752119, Ghasemi2021[article], 34819573)

Familial melanoma Benign:1

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.53	D
PhyloP100		4.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.063	T
Polyphen		1.0	D
Vest4		0.78
MVP		0.98
MPC		1.4
ClinPred		0.75	D
GERP RS		4.9
PromoterAI		-0.20	Neutral
Varity_R		0.83
gMVP		0.98
Mutation Taster		=2/98	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: rs775176191; hg19: chr9-21974744; COSMIC: COSV58709780; COSMIC: COSV58709780;