Genetic Variant CDKN2A:c.-31G>C (chr9-21974858-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000498124.1(CDKN2A):c.-31G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDKN2A
ENST00000498124.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.554

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_058195.4 link	c.194-3650G>C		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2	Q8N726-1
CDKN2A	NM_000077.5 link	c.-31G>C		upstream_gene_variant		ENST00000304494.10	NP_000068.1	P42771-1K7PML8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2 link	c.194-3650G>C		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1		Q8N726-1
CDKN2A	ENST00000304494.10 link	c.-31G>C		upstream_gene_variant		1	NM_000077.5	ENSP00000307101.5		P42771-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

124728

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1365428

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

673336

African (AFR)

AF:

0.00

AC:

AN:

29550

American (AMR)

AF:

0.00

AC:

AN:

29974

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22044

East Asian (EAS)

AF:

0.00

AC:

AN:

35530

South Asian (SAS)

AF:

0.00

AC:

AN:

74476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4276

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072620

Other (OTH)

AF:

0.00

AC:

AN:

56578

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.1

(source)

DANN

Benign

0.60

PhyloP100

-0.55

PromoterAI

-0.081

Neutral

(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

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over