rs36228836

Positions:

• chr9-21975142-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_058195.4(CDKN2A):​c.194-3934T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,207,918 control chromosomes in the GnomAD database, including 531 homozygotes. 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: 𝑓 0.0091 (103 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (428 hom.)
• Consequence: CDKN2A NM_058195.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.78

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.194-3934T>A		intron_variant		ENST00000579755.2	NP_478102.2
CDKN2A	NM_001363763.2	c.-3-3934T>A		intron_variant			NP_001350692.1
CDKN2A	XM_047422597.1	c.-3-3934T>A		intron_variant			XP_047278553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2	c.194-3934T>A		intron_variant		1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.00915 AC: 1390 AN: 151978 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.0683

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.00432

GnomAD4 exome AF: 0.00587 AC: 6198 AN: 1055820 Hom.: 428 Cov.: 32 AF XY: 0.00630 AC XY: 3129 AN XY: 496528

Gnomad4 AFR exome AF: 0.000416

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.000149

Gnomad4 EAS exome AF: 0.182

Gnomad4 SAS exome AF: 0.0604

Gnomad4 FIN exome AF: 0.0000634

Gnomad4 NFE exome AF: 0.000299

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.00913 AC: 1388 AN: 152098 Hom.: 103 Cov.: 32 AF XY: 0.0105 AC XY: 780 AN XY: 74338

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.0681

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000574

Gnomad4 OTH AF: 0.00523

Alfa AF: 0.00233 Hom.: 2

Bravo AF: 0.00890

Asia WGS AF: 0.0790 AC: 272 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.80
DANN	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs36228836; hg19: chr9-21975141;