rs749714198

Variant names:

• chr9-21971100-G-A
• rs749714198
• NM_000077.5:c.259C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-21971100-G-A
• chr9-21971100-G-C
• chr9-21971100-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 12P and 2B. PM1 PM5 PP5_Very_Strong BP4 BS2_Supporting

The NM_000077.5(CDKN2A):​c.259C>T​(p.Arg87Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,604,616 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. R87G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.952
• Publications: 25 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 10 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 45 uncertain in NM_000077.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-21971100-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2735264.
• PP5: Variant 9-21971100-G-A is Pathogenic according to our data. Variant chr9-21971100-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 406707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.221715). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.259C>T	p.Arg87Trp	missense	Exon 2 of 3	NP_000068.1	P42771-1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.302C>T	p.Pro101Leu	missense	Exon 2 of 3	NP_478102.2	Q8N726-1
	CDKN2A	NM_001195132.2		c.259C>T	p.Arg87Trp	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.259C>T	p.Arg87Trp	missense	Exon 2 of 3	ENSP00000307101.5	P42771-1
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.302C>T	p.Pro101Leu	missense	Exon 2 of 3	ENSP00000462950.1	Q8N726-1
	CDKN2A	ENST00000498124.1	TSL:1	c.259C>T	p.Arg87Trp	missense	Exon 2 of 4	ENSP00000418915.1	P42771-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000861 AC: 2 AN: 232208 AF XY: 0.0000156

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: 0.00000954

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1452390 Hom.: 0 Cov.: 31 AF XY: 0.00000692 AC XY: 5 AN XY: 722914

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44658

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5422

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111550

Other (OTH) AF: 0.00 AC: 0 AN: 60250

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000638 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000833 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Melanoma-pancreatic cancer syndrome (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)
1	-	-	Familial melanoma (1)
1	-	-	Familial meningioma (1)
1	-	-	Melanoma and neural system tumor syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.0072
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.50	T
PhyloP100		0.95
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.47
Sift	Benign	0.033	D
Sift4G	Uncertain	0.045	D
Vest4		0.22
MVP		0.91
ClinPred		0.69	D
GERP RS		5.0
PromoterAI		0.0081	Neutral
Varity_R		0.78
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: rs749714198; hg19: chr9-21971099; COSMIC: COSV58718452; COSMIC: COSV58718452;