9-21974706-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS1_Supporting

The NM_000077.5(CDKN2A):​c.122C>A​(p.Pro41Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P41P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

1
1
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:1

Conservation

PhyloP100: -0.965
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]

Genome browser will be placed here

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
BP4
Computational evidence support a benign effect (MetaRNN=0.1741842).
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000197 (3/152042) while in subpopulation EAS AF= 0.000581 (3/5166). AF 95% confidence interval is 0.000158. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDKN2ANM_000077.5 linkc.122C>A p.Pro41Gln missense_variant Exon 1 of 3 ENST00000304494.10 NP_000068.1 P42771-1K7PML8
CDKN2ANM_058195.4 linkc.194-3498C>A intron_variant Intron 1 of 2 ENST00000579755.2 NP_478102.2 Q8N726-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDKN2AENST00000304494.10 linkc.122C>A p.Pro41Gln missense_variant Exon 1 of 3 1 NM_000077.5 ENSP00000307101.5 P42771-1
CDKN2AENST00000579755.2 linkc.194-3498C>A intron_variant Intron 1 of 2 1 NM_058195.4 ENSP00000462950.1 Q8N726-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152042
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000581
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
GnomAD3 exomes
AF:
0.0000327
AC:
8
AN:
244752
Hom.:
0
AF XY:
0.0000150
AC XY:
2
AN XY:
133500
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000439
Gnomad SAS 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:
0.00000205
AC:
3
AN:
1460848
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726730
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152042
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000581
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Oct 02, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces proline with glutamine at codon 41 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An experimental functional study has reported this variant was neutral in a cell proliferation assay (PMID: 35001868). This variant has not been reported in individuals affected with CDKN2A-related disorders in the literature. This variant has been identified in 9/276116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Jan 27, 2023
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

Ovarian cancer Pathogenic:1
Jan 01, 2022
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University
Significance: Likely pathogenic
Review Status: flagged submission
Collection Method: clinical testing

- -

not specified Uncertain:1
Apr 04, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CDKN2A c.122C>A (p.Pro41Gln) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 244752 control chromosomes, predominantly at a frequency of 0.00044 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.122C>A has been reported in the literature in individuals affected with pancreatic ductal adenocarcinoma, also in control subjects (Xu_2015, Yin_2022, Okawa_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma . At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant by an in vitro cell proliferation assay (Kimura_2022). The following publications have been ascertained in the context of this evaluation (PMID: 27756164, 27960642, 28765326, 9166859, 35001868, 16818274, 18519632, 36243179, 7718873, 26104880, 35171259). ClinVar contains an entry for this variant (Variation ID: 141111). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Melanoma and neural system tumor syndrome Uncertain:1
Aug 06, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Jan 23, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies demonstrate neutral cell proliferation effects (Kimura et al., 2022); This variant is associated with the following publications: (PMID: 26104880, 35001868) -

Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial melanoma Uncertain:1
Dec 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 41 of the CDKN2A (p16INK4a) protein (p.Pro41Gln). This variant is present in population databases (rs373407950, gnomAD 0.05%). This missense change has been observed in individual(s) with pancreatic ductal adenocarcinoma and acute lymphoblastic leukemia (PMID: 26104880, 35171259). ClinVar contains an entry for this variant (Variation ID: 141111). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDKN2A (p16INK4a) function (PMID: 35001868). 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
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
14
DANN
Benign
0.96
DEOGEN2
Benign
0.11
T;T;.
Eigen
Benign
-0.84
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.22
N
LIST_S2
Benign
0.78
T;T;T
M_CAP
Pathogenic
0.50
D
MetaRNN
Benign
0.17
T;T;T
MetaSVM
Benign
-0.46
T
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.7
N;.;N
REVEL
Uncertain
0.49
Sift
Benign
0.48
T;.;T
Sift4G
Benign
0.66
T;T;T
Polyphen
0.95
P;.;.
Vest4
0.19
MVP
0.97
MPC
1.0
ClinPred
0.28
T
GERP RS
-3.8
Varity_R
0.054
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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: rs373407950; hg19: chr9-21974705; API