Genetic Variant CDKN2A:p.Ile49Thr (chr9-21974682-A-G) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 5P and 6B. PM1PM5PP5BP4BS1_SupportingBS2

The NM_000077.5(CDKN2A):c.146T>C(p.Ile49Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I49M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:10O:1

Conservation

PhyloP100: 5.56

Publications

38 publications found

Variant links:

COSMIC-nc: COSV58687879

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: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 12 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 chr9-21974682-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 430217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 9-21974682-A-G is Pathogenic according to our data. Variant chr9-21974682-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127523.

BP4

Computational evidence support a benign effect (MetaRNN=0.063048065). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000723 (11/152212) while in subpopulation AMR AF = 0.000654 (10/15292). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKN2A	NM_000077.5	MANE Select	c.146T>C	p.Ile49Thr	missense	Exon 1 of 3	NP_000068.1	P42771-1
CDKN2A	NM_058195.4	MANE Plus Clinical	c.194-3474T>C		intron	N/A	NP_478102.2	Q8N726-1
CDKN2A	NM_001195132.2		c.146T>C	p.Ile49Thr	missense	Exon 1 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.146T>C	p.Ile49Thr	missense	Exon 1 of 3	ENSP00000307101.5	P42771-1
CDKN2A	ENST00000498124.1	TSL:1	c.146T>C	p.Ile49Thr	missense	Exon 1 of 4	ENSP00000418915.1	P42771-4
CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.194-3474T>C		intron	N/A	ENSP00000462950.1	Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000625

AC:

156

AN:

249454

AF XY:

0.000489

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00451

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000114

AC:

167

AN:

1461744

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00369

AC:

165

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112004

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000723

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41536

American (AMR)

AF:

0.000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000120

Hom.:

Bravo

AF:

0.000298

ExAC

AF:

0.000436

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (4)

CDKN2A-related disorder (2)

Melanoma-pancreatic cancer syndrome (2)

not provided (2)

not specified (2)

Acute lymphoid leukemia (1)

Familial melanoma (1)

Melanoma and neural system tumor syndrome (1)

Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome (1)

Osteoblastic osteosarcoma (1)

Melanoma and neural system tumor syndrome;C1838547:Melanoma-pancreatic cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.063

MetaSVM

Uncertain

0.0011

PhyloP100

5.6

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.70

MVP

0.99

MPC

1.4

ClinPred

0.25

GERP RS

4.9

PromoterAI

-0.033

Neutral

(source)

Varity_R

0.49

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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