9-21971200-C-G

Variant names:

• chr9-21971200-C-G
• rs104894095
• NM_000077.5:c.159G>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 24P and 4B. PS1_Very_Strong PS3 PM1 PM5 PP5_Very_Strong BS2

The NM_000077.5(CDKN2A):​c.159G>C​(p.Met53Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,597,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000212879: Functional analyses of proteins harboring the p.M53I substitution have consistently demonstrated impaired binding to CDK4. In some cases, the variant protein was also shown to have reduced association with CDK6 and/or impaired growth and colony formation (Harland M et al. Hum. Mol. Genet., 1997 Nov" and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M53T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 5.60
• Publications: 80 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 20 ACMG points.

• PS1: Transcript NM_000077.5 (CDKN2A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000212879: Functional analyses of proteins harboring the p.M53I substitution have consistently demonstrated impaired binding to CDK4. In some cases, the variant protein was also shown to have reduced association with CDK6 and/or impaired growth and colony formation (Harland M et al. Hum. Mol. Genet., 1997 Nov;6:2061-7; Sun et al. Int J Cancer 1997; 73(4): 531-6; Walker et al. Int J Cancer 1999; 82(2): 305-12; Becker TM et al. Clin. Cancer Res. 2001 Oct;7(10):3282-8; McKenzie et al. Hum Mutat 2010; 31(6): 692-701).; SCV001353553: Functional studies reported defects in CDK binding, loss of cell cycle control and inhibition of cellular growth (PMID: 9328469, 9389568, 11595726, 20340136).; SCV000260919: Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 9328469, 9389568, 11595726).; SCV000210954: Published functional studies demonstrate a damaging effect: significantly reduced binding to CDK4 compared to wild-type (Sun 1997, Monzon 1998, Becker 2001, McKenzie 2010); SCV000601018: Functional studies have shown that this variant is disrupts CDKN2A's ability to effectively bind CDK4 (PMIDs: 20340136 (2010, 11595726 (2001), 9328469 (1997), and 9389568 (1997)).; SCV005361911: "In vitro experimental studies show this amino acid change impacts protein function (McKenzie et al. 2010. PubMed ID: 20340136; Figure 3. Monzon et al. 1998. PubMed ID: 9516223)."
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 48 uncertain in NM_000077.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-21971202-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1467708.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 9-21971200-C-G is Pathogenic according to our data. Variant chr9-21971200-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 9414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 27 AD gene.

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.159G>C	p.Met53Ile	missense	Exon 2 of 3	NP_000068.1	P42771-1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.202G>C	p.Asp68His	missense	Exon 2 of 3	NP_478102.2	Q8N726-1
	CDKN2A	NM_001195132.2		c.159G>C	p.Met53Ile	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.159G>C	p.Met53Ile	missense	Exon 2 of 3	ENSP00000307101.5	P42771-1
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.202G>C	p.Asp68His	missense	Exon 2 of 3	ENSP00000462950.1	Q8N726-1
	CDKN2A	ENST00000498124.1	TSL:1	c.159G>C	p.Met53Ile	missense	Exon 2 of 4	ENSP00000418915.1	P42771-4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152230 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000905 AC: 2 AN: 221078 AF XY: 0.00

Gnomad AFR exome AF: 0.0000749

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: 0.0000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000187 AC: 27 AN: 1445440 Hom.: 0 Cov.: 31 AF XY: 0.0000222 AC XY: 16 AN XY: 719514

African (AFR) AF: 0.0000299 AC: 1 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39570

South Asian (SAS) AF: 0.00 AC: 0 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1110994

Other (OTH) AF: 0.0000166 AC: 1 AN: 60160

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000167 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)
1	-	-	CDKN2A-related disorder (1)
1	-	-	Familial melanoma (1)
1	-	-	Melanoma and neural system tumor syndrome (1)
1	-	-	Melanoma-pancreatic cancer syndrome (1)
-	-	-	Melanoma, cutaneous malignant, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.43	T
PhyloP100		5.6
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.013	D
Vest4		0.47
MVP		0.97
ClinPred		0.94	D
GERP RS		5.8
PromoterAI		0.022	Neutral
Varity_R		0.79
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: rs104894095; hg19: chr9-21971199; COSMIC: COSV58703741; COSMIC: COSV58703741;