dbSNP rs36228836: CDKN2A:c.194-3934T>A (chr9-21975142-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_058195.4(CDKN2A):c.194-3934T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,207,918 control chromosomes in the GnomAD database, including 531 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0091 ( 103 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 428 hom. )

Consequence

CDKN2A
NM_058195.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.78

Publications

7 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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_058195.4 link	c.194-3934T>A	intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2	Q8N726-1
CDKN2A	NM_001363763.2 link	c.-3-3934T>A	intron_variant	Intron 1 of 2		NP_001350692.1
CDKN2A	XM_047422597.1 link	c.-3-3934T>A	intron_variant	Intron 1 of 2		XP_047278553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2 link	c.194-3934T>A		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.00915

AC:

1390

AN:

151978

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.189

Gnomad SAS

AF:

0.0683

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000574

Gnomad OTH

AF:

0.00432

GnomAD4 exome

AF:

0.00587

AC:

6198

AN:

1055820

Hom.:

428

Cov.:

AF XY:

0.00630

AC XY:

3129

AN XY:

496528

show subpopulations

African (AFR)

AF:

0.000416

AC:

AN:

21616

American (AMR)

AF:

0.00157

AC:

AN:

6988

Ashkenazi Jewish (ASJ)

AF:

0.000149

AC:

AN:

13464

East Asian (EAS)

AF:

0.182

AC:

3660

AN:

20092

South Asian (SAS)

AF:

0.0604

AC:

1738

AN:

28756

European-Finnish (FIN)

AF:

0.0000634

AC:

AN:

15772

Middle Eastern (MID)

AF:

0.00572

AC:

AN:

2798

European-Non Finnish (NFE)

AF:

0.000299

AC:

270

AN:

904130

Other (OTH)

AF:

0.0116

AC:

491

AN:

42204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

269

538

807

1076

1345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.00913

AC:

1388

AN:

152098

Hom.:

103

Cov.:

AF XY:

0.0105

AC XY:

780

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41534

American (AMR)

AF:

0.00177

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3466

East Asian (EAS)

AF:

0.188

AC:

963

AN:

5110

South Asian (SAS)

AF:

0.0681

AC:

328

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000574

AC:

AN:

67984

Other (OTH)

AF:

0.00523

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.00233

Hom.:

Bravo

AF:

0.00890

Asia WGS

AF:

0.0790

AC:

272

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.80

(source)

DANN

Benign

0.68

PhyloP100

-2.8

PromoterAI

0.091

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over