9-21971113-C-T

Variant names:

• chr9-21971113-C-T
• rs1060504181
• NM_058195.4:c.289G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4 BP6

The NM_058195.4(CDKN2A):​c.289G>A​(p.Ala97Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,452,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A97V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDKN2A NM_058195.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0300
• Publications: 7 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 16 uncertain in NM_058195.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-21971112-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376307.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BP4: Computational evidence support a benign effect (MetaRNN=0.26923096).
• BP6: Variant 9-21971113-C-T is Benign according to our data. Variant chr9-21971113-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 483328.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.289G>A	p.Ala97Thr	missense_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2
CDKN2A	NM_000077.5	c.246G>A	p.Val82Val	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.289G>A	p.Ala97Thr	missense_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1
CDKN2A	ENST00000304494.10	c.246G>A	p.Val82Val	synonymous_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000433 AC: 1 AN: 230976 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1452018 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722740

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5458

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111510

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

- -

Hereditary cancer-predisposing syndrome Benign:1

Jul 26, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	0.0014	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T;T
Eigen	Benign	-0.060
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.47	.;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.44	T
PhyloP100		-0.030
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.8	.;D
REVEL	Uncertain	0.39
Sift	Benign	0.11	.;T
Sift4G	Benign	0.35	T;T
Vest4		0.17
MVP		0.93
ClinPred		0.33	T
GERP RS		3.0
PromoterAI		0.032	Neutral
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs1060504181; hg19: chr9-21971112; COSMIC: COSV58722238;