chr9-21974680-G-A

Variant names:

• chr9-21974680-G-A
• rs864622636
• NM_000077.5:c.148C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.148C>T​(p.Gln50*) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000275624: The p.Q50* pathogenic mutation has also shown an inability to bind to Cdk4 and Cdk6 when assessed in vitro (Parry D et al. Mol. Cell. Biol. 1996 Jul" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q50Q) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDKN2A NM_000077.5 stop_gained, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 6.06
• Publications: 21 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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000275624: The p.Q50* pathogenic mutation has also shown an inability to bind to Cdk4 and Cdk6 when assessed in vitro (Parry D et al. Mol. Cell. Biol. 1996 Jul;16:3844-52).; SCV000568689: Consistent with predictions, Parry et al (1996) demonstrated via Cdk binding assays that this variant results in a truncated protein that is unable to bind to CDK2, CDK4, or CDK6.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21974680-G-A is Pathogenic according to our data. Variant chr9-21974680-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 220711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.148C>T	p.Gln50*	stop_gained splice_region	Exon 1 of 3	NP_000068.1	P42771-1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.194-3472C>T		intron	N/A	NP_478102.2	Q8N726-1
	CDKN2A	NM_058197.5		c.148C>T	p.Gln50*	stop_gained	Exon 1 of 3	NP_478104.2	P42771-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.148C>T	p.Gln50*	stop_gained splice_region	Exon 1 of 3	ENSP00000307101.5	P42771-1
	CDKN2A	ENST00000498124.1	TSL:1	c.148C>T	p.Gln50*	stop_gained splice_region	Exon 1 of 4	ENSP00000418915.1	P42771-4
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.194-3472C>T		intron	N/A	ENSP00000462950.1	Q8N726-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000216 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		6.1
Vest4		0.89
GERP RS		4.9
PromoterAI		-0.082	Neutral
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs864622636; hg19: chr9-21974679; COSMIC: COSV58683786; COSMIC: COSV58683786;