Genetic Variant NM_000077.5:c.442G>A (chr9-21970917-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:23O:1

Conservation

PhyloP100: 0.153

Publications

217 publications found

Variant links:

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

CDKN2A links:

ENSG00000264545 (HGNC:):

ENSG00000264545 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

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

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.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0249

AC XY:

18099

AN XY:

726302

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2229

4458

6688

8917

11146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1118

2236

3354

4472

5590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0197

AC:

2999

AN:

152342

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

1452

AN XY:

74504

show subpopulations

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:

AN:

5182

South Asian (SAS)

AF:

0.00765

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00508

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0310

AC:

2105

AN:

68010

Other (OTH)

AF:

0.0199

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

155

310

466

621

776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0279

Hom.:

299

Bravo

AF:

0.0199

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0293

AC:

113

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0321

AC:

276

ExAC

AF:

0.0224

AC:

2717

Asia WGS

AF:

0.00462

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

Hereditary cancer-predisposing syndrome (4)

not provided (4)

Melanoma-pancreatic cancer syndrome (3)

Familial melanoma (1)

Li-Fraumeni syndrome;C2931038:Familial pancreatic carcinoma (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

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.0

PhyloP100

0.15

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.86

REVEL

Benign

0.27

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.041

Polyphen

0.49

Vest4

0.092

MPC

0.39

ClinPred

0.012

GERP RS

1.1

PromoterAI

0.0080

Neutral

(source)

Varity_R

0.096

gMVP

0.38

Mutation Taster

=85/15

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over