9-21974721-G-C

Position:

• chr9-21974721-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000077.5(CDKN2A):​c.107C>G​(p.Ala36Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0740

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]

ENSG00000264545 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a repeat ANK 1 (size 29) in uniprot entity CDN2A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0065148175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.107C>G	p.Ala36Gly	missense_variant	1/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-3513C>G		intron_variant		ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.107C>G	p.Ala36Gly	missense_variant	1/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.194-3513C>G		intron_variant		1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00184 AC: 417 AN: 226718 Hom.: 0 AF XY: 0.00174 AC XY: 218 AN XY: 125140

Gnomad AFR exome AF: 0.000222

Gnomad AMR exome AF: 0.0000595

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000206

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.00247

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000317 AC: 46 AN: 1450698 Hom.: 0 Cov.: 32 AF XY: 0.0000402 AC XY: 29 AN XY: 721230

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000907

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.0000762

Gnomad4 SAS exome AF: 0.0000588

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.0000667

GnomAD4 genome Cov.: 32

ExAC AF: 0.00312 AC: 374

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;T;.
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.87	D;D;D
MetaRNN	Benign	0.0065	T;T;T
MetaSVM	Uncertain	0.20	D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.8	D;.;D
REVEL	Uncertain	0.51
Sift	Benign	0.090	T;.;D
Sift4G	Benign	0.20	T;T;T
Polyphen		0.94	P;.;.
Vest4		0.31
MVP		0.93
MPC		1.1
ClinPred		0.092	T
GERP RS		-0.49
Varity_R		0.21
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs200382984; hg19: chr9-21974720; COSMIC: COSV58688149; COSMIC: COSV58688149;