chr9-21975018-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_058195.4(CDKN2A):c.194-3810G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 1,380,732 control chromosomes in the GnomAD database, including 252,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 21585 hom., cov: 32)

Exomes 𝑓: 0.61 ( 231157 hom. )

Consequence

CDKN2A
NM_058195.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:3O:1

Conservation

PhyloP100: -0.170

Publications

26 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 9-21975018-C-T is Benign according to our data. Variant chr9-21975018-C-T is described in ClinVar as Benign. ClinVar VariationId is 873184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058195.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CDKN2A	NM_058195.4	MANE Plus Clinical	c.194-3810G>A	intron	N/A	NP_478102.2	Q8N726-1
CDKN2A	NM_001363763.2		c.-3-3810G>A	intron	N/A	NP_001350692.1	P42771-2
CDKN2A	NM_000077.5	MANE Select	c.-191G>A	upstream_gene	N/A	NP_000068.1	P42771-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.194-3810G>A	intron	N/A	ENSP00000462950.1	Q8N726-1
CDKN2A	ENST00000530628.2	TSL:5	c.194-3810G>A	intron	N/A	ENSP00000432664.2	Q8N726-1
CDKN2A	ENST00000494262.5	TSL:3	c.-3-3810G>A	intron	N/A	ENSP00000464952.1	P42771-2

Frequencies

GnomAD3 genomes

AF:

0.504

AC:

76522

AN:

151970

Hom.:

21594

Cov.:

show subpopulations

Gnomad AFR

AF:

0.233

Gnomad AMI

AF:

0.562

Gnomad AMR

AF:

0.476

Gnomad ASJ

AF:

0.582

Gnomad EAS

AF:

0.648

Gnomad SAS

AF:

0.617

Gnomad FIN

AF:

0.663

Gnomad MID

AF:

0.509

Gnomad NFE

AF:

0.626

Gnomad OTH

AF:

0.503

GnomAD4 exome

AF:

0.610

AC:

749192

AN:

1228644

Hom.:

231157

Cov.:

AF XY:

0.610

AC XY:

361760

AN XY:

593052

show subpopulations

African (AFR)

AF:

0.212

AC:

5041

AN:

23730

American (AMR)

AF:

0.454

AC:

5749

AN:

12660

Ashkenazi Jewish (ASJ)

AF:

0.579

AC:

9941

AN:

17158

East Asian (EAS)

AF:

0.681

AC:

20110

AN:

29528

South Asian (SAS)

AF:

0.617

AC:

33068

AN:

53570

European-Finnish (FIN)

AF:

0.662

AC:

20365

AN:

30740

Middle Eastern (MID)

AF:

0.576

AC:

1973

AN:

3428

European-Non Finnish (NFE)

AF:

0.619

AC:

622968

AN:

1007056

Other (OTH)

AF:

0.590

AC:

29977

AN:

50774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

14728

29456

44185

58913

73641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17722

35444

53166

70888

88610

<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:

0.503

AC:

76522

AN:

152088

Hom.:

21585

Cov.:

AF XY:

0.508

AC XY:

37727

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.232

AC:

9645

AN:

41490

American (AMR)

AF:

0.476

AC:

7274

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.582

AC:

2019

AN:

3468

East Asian (EAS)

AF:

0.648

AC:

3330

AN:

5138

South Asian (SAS)

AF:

0.617

AC:

2974

AN:

4822

European-Finnish (FIN)

AF:

0.663

AC:

7017

AN:

10590

Middle Eastern (MID)

AF:

0.500

AC:

147

AN:

294

European-Non Finnish (NFE)

AF:

0.626

AC:

42552

AN:

67980

Other (OTH)

AF:

0.500

AC:

1054

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1757

3514

5272

7029

8786

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

680

1360

2040

2720

3400

<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:

0.592

Hom.:

7136

Bravo

AF:

0.473

Asia WGS

AF:

0.584

AC:

2036

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Squamous cell lung carcinoma (1)

Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.9

(source)

DANN

Benign

0.88

PhyloP100

-0.17

PromoterAI

-0.024

Neutral

(source)

Mutation Taster

=299/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over