rs34968276

chr9-21971110-G-Achr9-21971110-G-Cchr9-21971110-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1 PM2 BP6

The NM_058195.4(CDKN2A):c.292C>T(p.Arg98Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000138 in 1,452,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R98R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDKN2A NM_058195.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 6.18

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 40 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 9-21971110-G-A is Benign according to our data. Variant chr9-21971110-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 631231.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_058195.4	c.292C>T	p.Arg98Ter	stop_gained	2/3	ENST00000579755.2
CDKN2A	NM_000077.5	c.249C>T	p.His83=	synonymous_variant	2/3	ENST00000304494.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000579755.2	c.292C>T	p.Arg98Ter	stop_gained	2/3	1	NM_058195.4
CDKN2A	ENST00000304494.10	c.249C>T	p.His83=	synonymous_variant	2/3	1	NM_000077.5	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452118 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722772

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 14, 2019	This 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 24, 2018	- -

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Benign	-0.42
Cadd	Benign	13
Dann	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A;A;D;D;D;D;D;D;D;D;D
Vest4		0.89
GERP RS		5.0

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

LitVar

Other links and lift over

dbSNP: rs34968276; hg19: chr9-21971109;