NM_000077.5:c.151-4G>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000077.5(CDKN2A):c.151-4G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000919 in 1,596,954 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00096 ( 29 hom. )

Consequence

CDKN2A
NM_000077.5 splice_region, intron

Scores

Splicing: ADA: 0.00001552

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: -0.120

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 links:

ENSG00000264545 (HGNC:):

ENSG00000264545 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

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

BP6

Variant 9-21971212-C-G is Benign according to our data. Variant chr9-21971212-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141600.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=9, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000538 (82/152316) while in subpopulation SAS AF= 0.0168 (81/4828). AF 95% confidence interval is 0.0138. There are 0 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 82 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5 link	c.151-4G>C		splice_region_variant, intron_variant	Intron 1 of 2	ENST00000304494.10	NP_000068.1	P42771-1K7PML8
CDKN2A	NM_058195.4 link	c.194-4G>C		splice_region_variant, 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
CDKN2A	ENST00000304494.10 link	c.151-4G>C		splice_region_variant, intron_variant	Intron 1 of 2	1	NM_000077.5	ENSP00000307101.5		P42771-1
CDKN2A	ENST00000579755.2 link	c.194-4G>C		splice_region_variant, intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152196

Hom.:

Cov.:

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:

0.00

Gnomad SAS

AF:

0.0168

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00200

AC:

439

AN:

219288

Hom.:

AF XY:

0.00257

AC XY:

314

AN XY:

122046

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0145

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000304

Gnomad OTH exome

AF:

0.000358

GnomAD4 exome

AF:

0.000959

AC:

1386

AN:

1444638

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

985

AN XY:

719038

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0152

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.000538

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000725

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0168

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000831

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Dec 23, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 27, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2014

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.194-4G>C intronic variant (also known as c.151-4G>C) results from a G to C substitution 4 nucleotides upstream from coding exon 2 in the CDKN2A gene. This alteration has been described in an individual diagnosed with early-onset hepatic carcinoma but hasn't been reported in melanoma cohorts to date (Chaubert P et al. Hepatology 1997; 25:1376-81). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. This nucleotide position is not well conserved in available vertebrate species. To date, this alteration has been detected with an allele frequency of approximately 0.16% (greater than 600 alleles tested) in our clinical cohort (includes this individual). Based on nucleotide sequence alignment, this position is well conserved in available vertebrate species.Using the BDGP and ESEfinder splice site prediction tools, this alteration does not have any significant effect on the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of c.676-5T>C remains unclear. -

not specified

Benign:3

Jan 10, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDKN2A: BP4, BS1, BS2 -

Jun 05, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CDKN2A c.151-4G>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. One functional study found that this variant does not affect splicing (Loo_Oncogene_2003). The variant of interest has been found in a large, broad control population, ExAC in 224/82416 control chromosomes (2 homozygotes) at a frequency of 0.0027179, which is approximately 9 times the estimated maximal expected allele frequency of a pathogenic CDKN2A variant (0.0003), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases recently classified this variant as likely benign/benign. Taken together, this variant is classified as benign. -

Melanoma-pancreatic cancer syndrome

Benign:2

Apr 20, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Aug 16, 2016

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome

Benign:1

Feb 18, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial melanoma

Benign:1

Jan 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hepatocellular carcinoma

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous c.151-4G>C variant in CDKN2A has been identified in an individual with hepatocellular carcinoma (PMID: 9185756), but has also been identified in >1% of South Asian chromosomes and 2 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant hepatocellular carcinoma. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

4.7

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000016

dbscSNV1_RF

Benign

0.0

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over