rs606231175

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM4BP6BS2

The NM_000077.5(CDKN2A):​c.9_32delGGCGGCGGGGAGCAGCATGGAGCC​(p.Ala4_Pro11del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000952 in 1,606,464 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: 2.62
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1
In a chain Cyclin-dependent kinase inhibitor 2A (size 155) in uniprot entity CDN2A_HUMAN there are 42 pathogenic changes around while only 12 benign (78%) in NM_000077.5
PM4
Nonframeshift variant in NON repetitive region in NM_000077.5.
BP6
Variant 9-21974795-AGGCTCCATGCTGCTCCCCGCCGCC-A is Benign according to our data. Variant chr9-21974795-AGGCTCCATGCTGCTCCCCGCCGCC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216277.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=9}.
BS2
High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDKN2ANM_000077.5 linkuse as main transcriptc.9_32delGGCGGCGGGGAGCAGCATGGAGCC p.Ala4_Pro11del disruptive_inframe_deletion 1/3 ENST00000304494.10 NP_000068.1 P42771-1K7PML8
CDKN2ANM_058195.4 linkuse as main transcriptc.194-3611_194-3588delGGCGGCGGGGAGCAGCATGGAGCC intron_variant ENST00000579755.2 NP_478102.2 Q8N726-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDKN2AENST00000304494.10 linkuse as main transcriptc.9_32delGGCGGCGGGGAGCAGCATGGAGCC p.Ala4_Pro11del disruptive_inframe_deletion 1/31 NM_000077.5 ENSP00000307101.5 P42771-1
CDKN2AENST00000579755.2 linkuse as main transcriptc.194-3611_194-3588delGGCGGCGGGGAGCAGCATGGAGCC intron_variant 1 NM_058195.4 ENSP00000462950.1 Q8N726-1

Frequencies

GnomAD3 genomes
AF:
0.000243
AC:
37
AN:
151972
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00210
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:
0.0000589
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000145
AC:
34
AN:
233942
Hom.:
0
AF XY:
0.000132
AC XY:
17
AN XY:
129094
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000525
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000112
Gnomad SAS exome
AF:
0.0000660
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000958
Gnomad OTH exome
AF:
0.000342
GnomAD4 exome
AF:
0.0000798
AC:
116
AN:
1454492
Hom.:
0
AF XY:
0.0000760
AC XY:
55
AN XY:
723908
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000493
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000581
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000720
Gnomad4 OTH exome
AF:
0.0000664
GnomAD4 genome
AF:
0.000243
AC:
37
AN:
151972
Hom.:
1
Cov.:
32
AF XY:
0.000377
AC XY:
28
AN XY:
74232
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00210
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000589
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000130
Hom.:
0
Bravo
AF:
0.000155
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Melanoma-pancreatic cancer syndrome Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Apr 20, 2023This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylSep 13, 2016- -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxOct 17, 2024In-frame deletion of 8 amino acid(s) in a non-repeat region; Observed in families with multiple cases of melanoma, demonstrating incomplete segregation with disease in at least one family, and in individuals with breast cancer (PMID: 10070944, 12072543, 17047042, 16905682, 20876876, 25780468, 25803691, 26976419, 35264596); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17047042, 25780468, 10070944, 12072543, 16905682, 19759551, 25803691, 26976419, 20876876, 27196769, 21325014, 28830827, 35264596, 28765326, 27756164, 27960642, 18519632, 16818274, 11159196, 9166859, 7718873, 15146471, 37059229, 37833309, 36243179) -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoNov 03, 2017- -
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 26, 2024Variant summary: CDKN2A c.9_32del24 (p.Ala4_Pro11del) results in an in-frame deletion that is predicted to remove 8 amino acids from the encoded protein. The variant allele was found at a frequency of 9.5e-05 in 1608632 control chromosomes, predominantly at a frequency of 0.0009 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma phenotype (0.0003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.9_32del24 has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma (Aitken_1999, Bishop_2002, Goldstein_2006, Goldstein_2007, Harland_2014, Wadt_2015, Cust_2011). However, these reports do not provide unequivocal conclusions about an association of the variant with Cutaneous Malignant Melanoma. The following publications have been ascertained in the context of this evaluation (PMID: 10070944, 12072543, 27756164, 27960642, 28765326, 21325014, 17047042, 15146471, 16905682, 25780468, 19759551, 9166859, 16818274, 18519632, 11159196, 7718873, 26976419, 25803691, 36243179, 35264596). ClinVar contains an entry for this variant (Variation ID: 216277). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalJul 31, 2024- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 21, 2023This variant results in a deletion of eight amino acids from the N-terminus of the CDKN2A (p16INK4A) protein. The residues deleted by this variant (p.Ala4_Pro11) are only present in human and two other non-human primate species. The mutant allele is a reference in other mammalian species (https://genome.ucsc.edu/). A functional study has shown that the mutant protein resulting from this variant retains normal protein function (PMID: 8668202). This variant has been reported in over ten individuals affected by melanoma (PMID: 10070944, 12072543, 16905682, 17047042, 19759551, 20876876, 21325014, 25780468, 25803691) and breast cancer (PMID: 26976419). This variant has also been identified in 36/265240 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and is particularly common in the Latino population (0.0512%, 18/35104 alleles). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 11, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Melanoma and neural system tumor syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 13, 2024- -
Familial melanoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 21, 2024This variant, c.9_32del, results in the deletion of 8 amino acid(s) of the CDKN2A (p16INK4a) protein (p.Ala4_Pro11del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs751570838, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with breast cancer and melanoma (PMID: 12072543, 16905682, 17047042, 19759551, 20876876, 25780468, 25803691, 26976419). ClinVar contains an entry for this variant (Variation ID: 216277). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587780668; hg19: chr9-21974794; API