9-21970917-C-T

Variant names:

• chr9-21970917-C-T
• rs3731249
• NM_000077.5:c.442G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000077.5(CDKN2A):​c.442G>A​(p.Ala148Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0244 in 1,612,214 control chromosomes in the GnomAD database, including 600 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A148P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (45 hom., cov: 32)
  • Exomes 𝑓: 0.025 (555 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:23 O:1
• Conservation: PhyloP100: 0.153
• Publications: 217 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 41 uncertain in NM_000077.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0030647516).
• BP6: Variant 9-21970917-C-T is Benign according to our data. Variant chr9-21970917-C-T is described in ClinVar as Benign. ClinVar VariationId is 41580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0197 (2999/152342) while in subpopulation NFE AF = 0.031 (2105/68010). AF 95% confidence interval is 0.0298. There are 45 homozygotes in GnomAd4. There are 1452 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2999 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.442G>A	p.Ala148Thr	missense	Exon 2 of 3	NP_000068.1	P42771-1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.*86G>A		3_prime_UTR	Exon 2 of 3	NP_478102.2	Q8N726-1
	CDKN2A	NM_001195132.2		c.442G>A	p.Ala148Thr	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.442G>A	p.Ala148Thr	missense	Exon 2 of 3	ENSP00000307101.5	P42771-1
	CDKN2A	ENST00000498124.1	TSL:1	c.442G>A	p.Ala148Thr	missense	Exon 2 of 4	ENSP00000418915.1	P42771-4
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.*86G>A		3_prime_UTR	Exon 2 of 3	ENSP00000462950.1	Q8N726-1

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2999 AN: 152224 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00492

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0309

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0209 AC: 5159 AN: 246916 AF XY: 0.0219

Gnomad AFR exome AF: 0.00360

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0302

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00548

Gnomad NFE exome AF: 0.0332

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0249 AC: 36385 AN: 1459872 Hom.: 555 Cov.: 31 AF XY: 0.0249 AC XY: 18099 AN XY: 726302

African (AFR) AF: 0.00448 AC: 150 AN: 33466

American (AMR) AF: 0.0166 AC: 744 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 760 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0105 AC: 909 AN: 86228

European-Finnish (FIN) AF: 0.00708 AC: 368 AN: 51976

Middle Eastern (MID) AF: 0.0315 AC: 169 AN: 5358

European-Non Finnish (NFE) AF: 0.0287 AC: 31859 AN: 1111962

Other (OTH) AF: 0.0236 AC: 1426 AN: 60326

GnomAD4 genome AF: 0.0197 AC: 2999 AN: 152342 Hom.: 45 Cov.: 32 AF XY: 0.0195 AC XY: 1452 AN XY: 74504

African (AFR) AF: 0.00490 AC: 204 AN: 41596

American (AMR) AF: 0.0258 AC: 395 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00765 AC: 37 AN: 4834

European-Finnish (FIN) AF: 0.00508 AC: 54 AN: 10626

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0310 AC: 2105 AN: 68010

Other (OTH) AF: 0.0199 AC: 42 AN: 2114

Alfa AF: 0.0279 Hom.: 299

Bravo AF: 0.0199

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0293 AC: 113

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0321 AC: 276

ExAC AF: 0.0224 AC: 2717

Asia WGS AF: 0.00462 AC: 16 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (10)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	not provided (4)
-	-	3	Melanoma-pancreatic cancer syndrome (3)
-	-	1	Familial melanoma (1)
-	-	1	Li-Fraumeni syndrome;C2931038:Familial pancreatic carcinoma (1)
-	-	1	Melanoma, cutaneous malignant, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.15
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.27
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.041	D
Polyphen		0.49	P
Vest4		0.092
MPC		0.39
ClinPred		0.012	T
GERP RS		1.1
PromoterAI		0.0080	Neutral
Varity_R		0.096
gMVP		0.38
Mutation Taster		=85/15	polymorphism (auto)

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: rs3731249; hg19: chr9-21970916; COSMIC: COSV58682793; COSMIC: COSV58682793;