rs36228834

Variant names:

• chr9-21975320-T-A
• rs36228834
• NM_058195.4:c.194-4112A>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 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]

CDKN2A Gene-Disease associations (from GenCC):

• melanoma, cutaneous malignant, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• melanoma-pancreatic cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial atypical multiple mole melanoma syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma and neural system tumor syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2994 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.194-4112A>T		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2
CDKN2A	NM_001363763.2	c.-3-4112A>T		intron_variant	Intron 1 of 2		NP_001350692.1
CDKN2A	XM_047422597.1	c.-3-4112A>T		intron_variant	Intron 1 of 2		XP_047278553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2	c.194-4112A>T		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1

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

African (AFR) AF: 0.00488 AC: 203 AN: 41572

American (AMR) AF: 0.0261 AC: 400 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0309 AC: 107 AN: 3460

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00791 AC: 38 AN: 4804

European-Finnish (FIN) AF: 0.00509 AC: 54 AN: 10604

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0308 AC: 2097 AN: 68002

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

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

Feb 28, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Dec 01, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.88
PhyloP100		0.94
PromoterAI		-0.030	Neutral
Mutation Taster		=100/0	polymorphism

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: rs36228834; hg19: chr9-21975319;