rs3088440

Variant names:

• chr9-21968160-G-A
• rs3088440
• NM_000077.5:c.*69C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000077.5(CDKN2A):​c.*69C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,372,012 control chromosomes in the GnomAD database, including 10,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1606 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9083 hom.)
• Consequence: CDKN2A NM_000077.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.05
• Publications: 137 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 9-21968160-G-A is Benign according to our data. Variant chr9-21968160-G-A is described in ClinVar as Benign. ClinVar VariationId is 1227284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000077.5. 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_000077.5	MANE Select	c.*69C>T		3_prime_UTR	Exon 3 of 3	NP_000068.1	P42771-1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.*184C>T		3_prime_UTR	Exon 3 of 3	NP_478102.2	Q8N726-1
	CDKN2A	NM_001195132.2		c.*233C>T		3_prime_UTR	Exon 4 of 4	NP_001182061.1	P42771-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.*69C>T		3_prime_UTR	Exon 3 of 3	ENSP00000307101.5	P42771-1
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.*184C>T		3_prime_UTR	Exon 3 of 3	ENSP00000462950.1	Q8N726-1
	CDKN2A	ENST00000498124.1	TSL:1	c.*233C>T		3_prime_UTR	Exon 4 of 4	ENSP00000418915.1	P42771-4

Frequencies

GnomAD3 genomes AF: 0.132 AC: 19950 AN: 151564 Hom.: 1601 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.0885

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0845

Gnomad OTH AF: 0.121

GnomAD4 exome AF: 0.106 AC: 129199 AN: 1220332 Hom.: 9083 Cov.: 17 AF XY: 0.105 AC XY: 64948 AN XY: 617492

African (AFR) AF: 0.173 AC: 4985 AN: 28836

American (AMR) AF: 0.365 AC: 15779 AN: 43222

Ashkenazi Jewish (ASJ) AF: 0.0984 AC: 2409 AN: 24470

East Asian (EAS) AF: 0.105 AC: 4034 AN: 38388

South Asian (SAS) AF: 0.159 AC: 12641 AN: 79392

European-Finnish (FIN) AF: 0.112 AC: 5925 AN: 52702

Middle Eastern (MID) AF: 0.0732 AC: 376 AN: 5138

European-Non Finnish (NFE) AF: 0.0861 AC: 77133 AN: 895652

Other (OTH) AF: 0.113 AC: 5917 AN: 52532

GnomAD4 genome AF: 0.132 AC: 19992 AN: 151680 Hom.: 1606 Cov.: 32 AF XY: 0.135 AC XY: 10026 AN XY: 74098

African (AFR) AF: 0.175 AC: 7223 AN: 41318

American (AMR) AF: 0.253 AC: 3862 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0885 AC: 307 AN: 3470

East Asian (EAS) AF: 0.125 AC: 641 AN: 5142

South Asian (SAS) AF: 0.166 AC: 794 AN: 4796

European-Finnish (FIN) AF: 0.106 AC: 1118 AN: 10520

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0845 AC: 5737 AN: 67868

Other (OTH) AF: 0.120 AC: 253 AN: 2106

Alfa AF: 0.109 Hom.: 453

Bravo AF: 0.146

Asia WGS AF: 0.161 AC: 558 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.32
DANN	Benign	0.70
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3088440;

hg19: chr9-21968159;

COSMIC: COSV58724777;