rs6413464

chr9-21970980-C-Achr9-21970980-C-Gchr9-21970980-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000077.5(CDKN2A):c.379G>T(p.Ala127Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000951 in 1,610,798 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A127P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0049 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 2.90

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 -16 ACMG points.

• PM1: In a chain Cyclin-dependent kinase inhibitor 2A (size 155) in uniprot entity CDN2A_HUMAN there are 117 pathogenic changes around while only 31 benign (79%) in NM_000077.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-21970980-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 571866.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0074276924).
• BP6: Variant 9-21970980-C-A is Benign according to our data. Variant chr9-21970980-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 41578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21970980-C-A is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00488 (743/152354) while in subpopulation AFR AF= 0.0161 (671/41588). AF 95% confidence interval is 0.0151. There are 6 homozygotes in gnomad4. There are 331 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 741 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.379G>T	p.Ala127Ser	missense_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.*23G>T		3_prime_UTR_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.379G>T	p.Ala127Ser	missense_variant	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.*23G>T		3_prime_UTR_variant	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes AF: 0.00487 AC: 741 AN: 152236 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00129 AC: 316 AN: 244500 Hom.: 0 AF XY: 0.000991 AC XY: 132 AN XY: 133184

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000544

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000541 AC: 789 AN: 1458444 Hom.: 7 Cov.: 31 AF XY: 0.000445 AC XY: 323 AN XY: 725684

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00488 AC: 743 AN: 152354 Hom.: 6 Cov.: 32 AF XY: 0.00444 AC XY: 331 AN XY: 74506

Gnomad4 AFR AF: 0.0161

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.00611

ESP6500AA AF: 0.0161 AC: 71

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00155 AC: 188

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2018	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2018	This variant is associated with the following publications: (PMID: 26650189, 28944238, 18983535, 25780468, 7970734, 26104880, 22703879, 22995991, 25064638, 15860862, 20981092, 24728327, 9823374, 19141585, 26775776, 7777061, 10498896, 21462282, 12485439, 29552713, 20505745, 18573309) -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 26, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2016	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 10, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 26, 2020	- -

Melanoma-pancreatic cancer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 15, 2022

- -

Familial melanoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;.;.;.;.;T;.
Eigen	Benign	0.015
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.58	T;T;.;T;.;T;T;T
MetaRNN	Benign	0.0064	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	D;D;D;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N;.;.;N;.;.;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.036	D;.;.;T;.;.;.;.
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T
Polyphen		0.98	D;.;.;.;.;.;.;.
Vest4		0.29
MVP		0.97
MPC		0.69
ClinPred		0.023	T
GERP RS		4.9
Varity_R		0.17
gMVP		0.57

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: rs6413464; hg19: chr9-21970979; COSMIC: COSV58713816; COSMIC: COSV58713816;