rs199888003

Positions:

• chr9-21971041-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_058195.4(CDKN2A):​c.361G>A​(p.Ala121Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,605,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A121V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: CDKN2A NM_058195.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:10
• Conservation: PhyloP100: 0.312

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_benign. Variant got -5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 14 uncertain in NM_058195.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.09876472).
• BP6: Variant 9-21971041-C-T is Benign according to our data. Variant chr9-21971041-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135826.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=4, Uncertain_significance=5}. Variant chr9-21971041-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_058195.4	c.361G>A	p.Ala121Thr	missense_variant	2/3	ENST00000579755.2
CDKN2A	NM_000077.5	c.318G>A	p.Val106=	synonymous_variant	2/3	ENST00000304494.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000579755.2	c.361G>A	p.Ala121Thr	missense_variant	2/3	1	NM_058195.4
CDKN2A	ENST00000304494.10	c.318G>A	p.Val106=	synonymous_variant	2/3	1	NM_000077.5	P2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000221 AC: 52 AN: 235136 Hom.: 0 AF XY: 0.000201 AC XY: 26 AN XY: 129154

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000489

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000327 AC: 475 AN: 1453468 Hom.: 0 Cov.: 31 AF XY: 0.000322 AC XY: 233 AN XY: 723350

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000411

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74378

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000300 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000109 AC: 13

EpiCase AF: 0.000327

EpiControl AF: 0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 20, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2023	Observed in several individuals with melanoma, pancreatic cancer, or other cancers (PMID: 16234564, 17255954, 17218939, 21150883, 25787093, 26225579, 25479140, 26104880, 25980754, 26681309, 28726808, 34326862); In silico analysis supports a deleterious effect on protein structure/function; Reported using an alternate transcript of the gene; Also known as p.Ala162Thr; This variant is associated with the following publications: (PMID: 25064638, 25980754, 30709382, 30039340, 16234564, 21150883, 26104880, 17218939, 12538475, 25787093, 26225579, 17255954, 28726808, 29415044, 27621404, 26681309, 19690981, 25780468, 27882345, 25479140, 16896043, 29641532, 11687599, 8710906, 16818274, 12532425, 27756164, 37322831, 28765326, 34326862, 27960642) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	CDKN2A: BP4 -

not specified Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 04, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 19, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 10, 2014	Insufficient or inconclusive evidence -

Maffucci syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

-

- -

Melanoma-pancreatic cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Familial melanoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Benign	0.080	T;T
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.74	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-0.53	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N;N;N
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.054	T;T
Vest4		0.099
MVP		0.93
ClinPred		0.12	T
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199888003; hg19: chr9-21971040; COSMIC: COSV58712542; COSMIC: COSV58712542;