rs181044510

chr9-21968733-G-Achr9-21968733-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000498124.1(CDKN2A):c.496C>T(p.His166Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000933 in 1,536,164 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (11 hom.)
• Consequence: CDKN2A ENST00000498124.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:1
• Conservation: PhyloP100: -0.385

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018141866).
• BP6: Variant 9-21968733-G-A is Benign according to our data. Variant chr9-21968733-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133880.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_benign=2, Benign=1}.
• BS2: High AC in GnomAd at 329 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.458-491C>T		intron_variant		ENST00000304494.10
CDKN2A	NM_058195.4	c.*102-491C>T		intron_variant		ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.458-491C>T		intron_variant		1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.*102-491C>T		intron_variant		1	NM_058195.4

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 329 AN: 152220 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00138 AC: 186 AN: 134580 Hom.: 1 AF XY: 0.00124 AC XY: 91 AN XY: 73302

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00181

Gnomad SAS exome AF: 0.0000889

Gnomad FIN exome AF: 0.0271

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.000724

GnomAD4 exome AF: 0.000798 AC: 1104 AN: 1383826 Hom.: 11 Cov.: 32 AF XY: 0.000773 AC XY: 528 AN XY: 682858

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00148

Gnomad4 SAS exome AF: 0.0000505

Gnomad4 FIN exome AF: 0.0236

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152338 Hom.: 3 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74490

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0271

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000933 Hom.: 0

Bravo AF: 0.000317

ExAC AF: 0.000279 AC: 5

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 24728327) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CDKN2A: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Melanoma-pancreatic cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Counsyl

Oct 26, 2016

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	2.3
Dann	Benign	0.85
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PROVEAN	Benign	-0.030	N
Sift	Benign	0.077	T
Vest4		0.15
MVP		0.94
MPC		0.45
ClinPred		0.0092	T
GERP RS		-5.6
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs181044510; hg19: chr9-21968732; COSMIC: COSV105891472; COSMIC: COSV105891472;