rs36228834

Positions:

• chr9-21975320-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_058195.4(CDKN2A):​c.194-4112A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 152,236 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.020 (43 hom., cov: 31)
• Consequence: CDKN2A NM_058195.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.944

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 9-21975320-T-A is Benign according to our data. Variant chr9-21975320-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 223663.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0197 (2994/152236) while in subpopulation NFE AF= 0.0308 (2097/68002). AF 95% confidence interval is 0.0297. There are 43 homozygotes in gnomad4. There are 1454 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2994 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.194-4112A>T		intron_variant		ENST00000579755.2	NP_478102.2
CDKN2A	NM_001363763.2	c.-3-4112A>T		intron_variant			NP_001350692.1
CDKN2A	XM_047422597.1	c.-3-4112A>T		intron_variant			XP_047278553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2	c.194-4112A>T		intron_variant		1	NM_058195.4	ENSP00000462950
CDKN2A	ENST00000494262.5	c.-3-4112A>T		intron_variant		3		ENSP00000464952
CDKN2A	ENST00000498628.6	c.-3-4112A>T		intron_variant		2		ENSP00000467857
CDKN2A	ENST00000530628.2	c.194-4112A>T		intron_variant		5		ENSP00000432664

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2994 AN: 152118 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00770

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0308

Gnomad OTH AF: 0.0196

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0197 AC: 2994 AN: 152236 Hom.: 43 Cov.: 31 AF XY: 0.0195 AC XY: 1454 AN XY: 74456

Gnomad4 AFR AF: 0.00488

Gnomad4 AMR AF: 0.0261

Gnomad4 ASJ AF: 0.0309

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00791

Gnomad4 FIN AF: 0.00509

Gnomad4 NFE AF: 0.0308

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0240 Hom.: 3

Bravo AF: 0.0199

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2019

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Dec 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.88

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: rs36228834; hg19: chr9-21975319;