9-21994240-G-C

Variant names:

• chr9-21994240-G-C
• rs528789830
• NM_058195.4:c.92C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_058195.4(CDKN2A):​c.92C>G​(p.Thr31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,605,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 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. T31M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CDKN2A NM_058195.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.79
• Publications: 5 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015270889).
• BP6: Variant 9-21994240-G-C is Benign according to our data. Variant chr9-21994240-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 265298.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000263 (4/151972) while in subpopulation EAS AF = 0.000785 (4/5098). AF 95% confidence interval is 0.000268. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

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.92C>G	p.Thr31Arg	missense	Exon 1 of 3	NP_478102.2	Q8N726-1
	CDKN2A	NM_001363763.2		c.-4+581C>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.92C>G	p.Thr31Arg	missense	Exon 1 of 3	ENSP00000462950.1	Q8N726-1
	CDKN2A	ENST00000530628.2	TSL:5	c.92C>G	p.Thr31Arg	missense	Exon 1 of 3	ENSP00000432664.2	Q8N726-1
	CDKN2A	ENST00000494262.5	TSL:3	c.-175-187C>G		intron	N/A	ENSP00000464952.1	P42771-2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151852 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000783

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000908 AC: 21 AN: 231346 AF XY: 0.0000936

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1453270 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 723108

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39660

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5328

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111092

Other (OTH) AF: 0.00 AC: 0 AN: 60134

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151972 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74270

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000785 AC: 4 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67942

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000108 AC: 13

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.96	T
PhyloP100		1.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.12
Sift	Benign	0.31	T
Sift4G	Benign	0.58	T
Vest4		0.19
MVP		0.89
ClinPred		0.89	D
GERP RS		3.3
PromoterAI		0.0096	Neutral
Mutation Taster		=15/85	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: rs528789830; hg19: chr9-21994239;