9-21994141-G-C

Variant names:

• chr9-21994141-G-C
• rs1348413029
• NM_058195.4:c.191C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_058195.4(CDKN2A):​c.191C>G​(p.Pro64Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P64L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDKN2A NM_058195.4 missense, splice_region
• Scores: Splicing: ADA: 0.6825
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.58
• 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]

CDKN2B-AS1 (HGNC:34341): (CDKN2B antisense RNA 1) This gene is located within the CDKN2B-CDKN2A gene cluster at chromosome 9p21. The gene product is a functional RNA molecule that interacts with polycomb repressive complex-1 (PRC1) and -2 (PRC2), leading to epigenetic silencing of other genes in this cluster. This region is a significant genetic susceptibility locus for cardiovascular disease, and has also been linked to a number of other pathologies, including several cancers, intracranial aneurysm, type-2 diabetes, periodontitis, Alzheimer's disease, endometriosis, frailty in the elderly, and glaucoma. Multiple alternatively processed transcript variants have been detected, some of which may take the form of circular RNA molecules (PMID:21151960). [provided by RefSeq, May 2014]

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 33 uncertain in NM_058195.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3200336).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058195.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.191C>G	p.Pro64Arg	missense splice_region	Exon 1 of 3	NP_478102.2	Q8N726-1
	CDKN2A	NM_001363763.2		c.-4+680C>G		intron	N/A	NP_001350692.1	P42771-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.191C>G	p.Pro64Arg	missense splice_region	Exon 1 of 3	ENSP00000462950.1	Q8N726-1
	CDKN2A	ENST00000530628.2	TSL:5	c.191C>G	p.Pro64Arg	missense splice_region	Exon 1 of 3	ENSP00000432664.2	Q8N726-1
	CDKN2A	ENST00000494262.5	TSL:3	c.-175-88C>G		intron	N/A	ENSP00000464952.1	P42771-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448702 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 721280

African (AFR) AF: 0.00 AC: 0 AN: 33462

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111784

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	Familial melanoma (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.15	T
PhyloP100		2.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.014	D
Vest4		0.27
MVP		0.99
ClinPred		0.96	D
GERP RS		4.2
PromoterAI		0.0086	Neutral
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.68
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		0.12		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: rs1348413029; hg19: chr9-21994140;