rs104894099

Variant names:

• chr9-21971183-A-C
• rs104894099
• NM_000077.5:c.176T>G

Your query was ambiguous. Multiple possible variants found:

• chr9-21971183-A-C
• chr9-21971183-A-G
• chr9-21971183-A-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

The NM_000077.5(CDKN2A):​c.176T>G​(p.Val59Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,444,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V59A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 6.84
• Publications: 41 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 41 uncertain in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21971183-A-C is Pathogenic according to our data. Variant chr9-21971183-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 9423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2724597). . Strength limited to SUPPORTING due to the PP5.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	NM_000077.5	MANE Select	c.176T>G	p.Val59Gly	missense	Exon 2 of 3	NP_000068.1	P42771-1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.219T>G	p.Ser73Arg	missense	Exon 2 of 3	NP_478102.2	Q8N726-1
	CDKN2A	NM_001195132.2		c.176T>G	p.Val59Gly	missense	Exon 2 of 4	NP_001182061.1	P42771-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.176T>G	p.Val59Gly	missense	Exon 2 of 3	ENSP00000307101.5	P42771-1
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.219T>G	p.Ser73Arg	missense	Exon 2 of 3	ENSP00000462950.1	Q8N726-1
	CDKN2A	ENST00000498124.1	TSL:1	c.176T>G	p.Val59Gly	missense	Exon 2 of 4	ENSP00000418915.1	P42771-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000456 AC: 1 AN: 219096 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1444950 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 719186

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.0000225 AC: 1 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.00 AC: 0 AN: 85856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39198

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5594

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110742

Other (OTH) AF: 0.0000166 AC: 1 AN: 60086

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000838 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Melanoma-pancreatic cancer syndrome (3)
3	-	-	not provided (3)
2	-	-	Familial melanoma (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Melanoma and neural system tumor syndrome (1)
1	-	-	Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome (1)
1	-	-	Melanoma, cutaneous malignant, susceptibility to, 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.0071	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.86	T
PhyloP100		6.8
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.19
Sift	Benign	0.29	T
Sift4G	Benign	0.43	T
Vest4		0.31
MVP		0.99
ClinPred		0.81	D
GERP RS		4.7
PromoterAI		0.059	Neutral
Varity_R		0.74
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs104894099; hg19: chr9-21971182; COSMIC: COSV58728660;