9-21971167-C-A

Variant names:

• chr9-21971167-C-A
• rs876659128
• NM_058195.4:c.235G>T

Variant summary

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

The NM_058195.4(CDKN2A):​c.235G>T​(p.Ala79Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000693 in 1,442,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. A79P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CDKN2A NM_058195.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.73
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• melanoma, cutaneous malignant, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• melanoma-pancreatic cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial atypical multiple mole melanoma syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma and neural system tumor syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 18 benign, 32 uncertain in NM_058195.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.19759834).
• BP6: Variant 9-21971167-C-A is Benign according to our data. Variant chr9-21971167-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 231385.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.235G>T	p.Ala79Ser	missense_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2
CDKN2A	NM_000077.5	c.192G>T	p.Leu64Leu	synonymous_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2	c.235G>T	p.Ala79Ser	missense_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1
CDKN2A	ENST00000304494.10	c.192G>T	p.Leu64Leu	synonymous_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000693 AC: 10 AN: 1442940 Hom.: 0 Cov.: 31 AF XY: 0.00000696 AC XY: 5 AN XY: 718012

African (AFR) AF: 0.00 AC: 0 AN: 33300

American (AMR) AF: 0.00 AC: 0 AN: 44232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.00 AC: 0 AN: 85676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5374

European-Non Finnish (NFE) AF: 0.00000901 AC: 10 AN: 1109806

Other (OTH) AF: 0.00 AC: 0 AN: 59922

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Jan 08, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.192G>T variant (also known as p.L64L), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 192 and does not change the amino acid at position 64 of the p16 isoform. Of note, this variant is also known as p.A79S (c.235G>T) in the p14(ARF) isoform and results from a G to T substitution at nucleotide position 235. The evidence supporting a relationship between p14(ARF) and melanoma-pancreatic cancer syndrome is limited; therefore, the association of this variant with this gene-disease relationship is unknown. However, the association of this variant in the p16 isoform with melanoma-pancreatic cancer syndrome is unlikely. -

Familial melanoma Uncertain:1

Sep 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	9.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.53	.;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.78	T
PhyloP100		1.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	.;N
REVEL	Benign	0.16
Sift	Benign	0.15	.;T
Sift4G	Benign	0.28	T;T
Vest4		0.22
MVP		0.87
ClinPred		0.29	T
GERP RS		3.9
PromoterAI		-0.0032	Neutral
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs876659128; hg19: chr9-21971166;