9-21971044-G-A

Variant names:

• chr9-21971044-G-A
• rs763269347
• NM_058195.4:c.358C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_058195.4(CDKN2A):​c.358C>T​(p.Arg120Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 1,453,282 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict 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. R120S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (1 hom.)
• Consequence: CDKN2A NM_058195.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.674
• Publications: 11 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: Benign. The variant received -7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 19 benign, 32 uncertain in NM_058195.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.055409282).
• BP6: Variant 9-21971044-G-A is Benign according to our data. Variant chr9-21971044-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 823962.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058195.4. 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_058195.4	MANE Plus Clinical	c.358C>T	p.Arg120Cys	missense	Exon 2 of 3	NP_478102.2
	CDKN2A	NM_000077.5	MANE Select	c.315C>T	p.Asp105Asp	synonymous	Exon 2 of 3	NP_000068.1
	CDKN2A	NM_001195132.2		c.315C>T	p.Asp105Asp	synonymous	Exon 2 of 4	NP_001182061.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.358C>T	p.Arg120Cys	missense	Exon 2 of 3	ENSP00000462950.1
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.315C>T	p.Asp105Asp	synonymous	Exon 2 of 3	ENSP00000307101.5
	CDKN2A	ENST00000498124.1	TSL:1	c.315C>T	p.Asp105Asp	synonymous	Exon 2 of 4	ENSP00000418915.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000851 AC: 2 AN: 234900 AF XY: 0.00000775

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: 0.00000942

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000619 AC: 9 AN: 1453282 Hom.: 1 Cov.: 31 AF XY: 0.00000830 AC XY: 6 AN XY: 723252

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5204

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111308

Other (OTH) AF: 0.00 AC: 0 AN: 60184

GnomAD4 genome Cov.: 32

Alfa AF: 0.000184 Hom.: 1

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial melanoma Uncertain:1

Sep 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Dec 16, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico models in agreement (benign);Other strong data supporting benign classification

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	7.3
DANN	Benign	0.97
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.67
PROVEAN	Benign	3.6	N
REVEL	Benign	0.17
Sift	Benign	0.22	T
Sift4G	Benign	0.15	T
Vest4		0.13
MVP		0.50
ClinPred		0.038	T
GERP RS		-5.5
PromoterAI		-0.037	Neutral
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs763269347; hg19: chr9-21971043; COSMIC: COSV58684238; COSMIC: COSV58684238;