9-21974757-C-G

Variant names:

• chr9-21974757-C-G
• rs104894097
• NM_000077.5:c.71G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PS3 PM1 PP3_Moderate PP5_Very_Strong BS2

The NM_000077.5(CDKN2A):​c.71G>C​(p.Arg24Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000808 in 1,609,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000218160: Functional studies have shown that p.R24P mutants have varying levels of decreased binding affinity to CDK4 while other assays measuring cell cycle arrest and oxidative regulation have demonstrated activity comparable to wild type (Miller PJ et al. Hum. Mutat. 2011 Aug" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 0.147
• Publications: 75 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 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000218160: Functional studies have shown that p.R24P mutants have varying levels of decreased binding affinity to CDK4 while other assays measuring cell cycle arrest and oxidative regulation have demonstrated activity comparable to wild type (Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11; McKenzie HA et al. Hum. Mutat. 2010 Jun;31(6):692-701; Jenkins NC et al. J. Invest. Dermatol. 2013 Apr;133(4):1043-51; Monzon J et al. N. Engl. J. Med. 1998 Mar;338(13):879-87, Becker TM et al. Clin. Cancer Res. 2001 Oct;7(10):3282-8; Jones R et al. Cancer Res. 2007 Oct;67(19):9134-41).; SCV000684536: Functional studies have shown that this variant causes loss of p16INK4A binding to CDK4 and loss of cell cycle inhibition function (PMID: 17909018, 15945100, 19260062, 20340136, 11595726, 18843795).; SCV000292535: Published functional studies demonstrate a damaging effect: impaired binding to CDK4, impaired growth inhibition, and altered cellular localization (Monzon et al., 1998; Becker et al., 2001; McKenzie et al., 2010); PMID: 9516223, 10398427, 9823374, 9699728, 33945383, 29922827, 11595726, 21462282, 23190892, 16234564, 8570179, 9425228, 26845104, 11500805, 26775776, 15945100, 18843795, 26225579, 25356972, 26206375, 15235029, 28830827, 9328469, 15304099, 15146471, 9856841, 10390011, 12072543, 11815963, 21150883, 17218939, 21801156, 16905682, 18363633, 17047042, 26800492, 29506128, 31382929, 34308366, 32482799, 14646620, 30967399, 33050356, 30218143, 27535533, 11556834, 20340136; SCV006325056: Functional studies indicates that this missense change affects CDKN2A function (PMID: 11595726, 15945100, 18843795, 20340136, 23190892).; SCV004018546: Functional studies indicate this variant impacts protein function [PMID: 17909018].; SCV006311220: Experimental studies have shown that this missense change disrupts p16INK4a protein function, including cellular localization, CDK4 binding, and normal growth suppression (PMID:20340136, 23190892, 11595726, 18843795, 15945100).; SCV000545544: Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 11595726, 15945100, 18843795, 20340136, 23190892).
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 42 uncertain in NM_000077.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• PP5: Variant 9-21974757-C-G is Pathogenic according to our data. Variant chr9-21974757-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 9415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 11 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.71G>C	p.Arg24Pro	missense	Exon 1 of 3	NP_000068.1	P42771-1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.194-3549G>C		intron	N/A	NP_478102.2	Q8N726-1
	CDKN2A	NM_001195132.2		c.71G>C	p.Arg24Pro	missense	Exon 1 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.71G>C	p.Arg24Pro	missense	Exon 1 of 3	ENSP00000307101.5	P42771-1
	CDKN2A	ENST00000498124.1	TSL:1	c.71G>C	p.Arg24Pro	missense	Exon 1 of 4	ENSP00000418915.1	P42771-4
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.194-3549G>C		intron	N/A	ENSP00000462950.1	Q8N726-1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151922 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: 0.0000169 AC: 4 AN: 236656 AF XY: 0.00000767

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: 0.0000380

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1457942 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 725456

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111504

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151922 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74182

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41374

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000253 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Melanoma-pancreatic cancer syndrome (8)
4	-	-	not provided (4)
3	-	-	Hereditary cancer-predisposing syndrome (3)
1	-	-	Familial melanoma (1)
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)
-	-	-	Melanoma, cutaneous malignant, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.049
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.73	T
PhyloP100		0.15
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.40
Sift	Benign	0.14	T
Sift4G	Benign	0.21	T
Polyphen		0.99	D
Vest4		0.68
MutPred		0.67		Loss of MoRF binding (P = 0.0099)
MVP		0.98
MPC		1.2
ClinPred		0.86	D
GERP RS		3.0
PromoterAI		-0.012	Neutral
Varity_R		0.54
gMVP		0.96
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs104894097; hg19: chr9-21974756; COSMIC: COSV58704208; COSMIC: COSV58704208;