rs1800586

Variant names:

• chr9-21974861-C-A
• rs1800586
• ENST00000498124.1:c.-34G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-21974861-C-A
• chr9-21974861-C-G
• chr9-21974861-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PP5_Very_Strong BP4 BS2

The ENST00000498124.1(CDKN2A):​c.-34G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000603 in 1,509,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: CDKN2A ENST00000498124.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: -0.827
• Publications: 45 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PP5: Variant 9-21974861-C-A is Pathogenic according to our data. Variant chr9-21974861-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 182414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAdExome4 at 89 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000498124.1. 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_058195.4	MANE Plus Clinical	c.194-3653G>T		intron	N/A	NP_478102.2	Q8N726-1
	CDKN2A	NM_001363763.2		c.-3-3653G>T		intron	N/A	NP_001350692.1	P42771-2
	CDKN2A	NM_000077.5	MANE Select	c.-34G>T		upstream_gene	N/A	NP_000068.1	P42771-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000498124.1	TSL:1	c.-34G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000418915.1	P42771-4
	CDKN2A	ENST00000498124.1	TSL:1	c.-34G>T		5_prime_UTR	Exon 1 of 4	ENSP00000418915.1	P42771-4
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.194-3653G>T		intron	N/A	ENSP00000462950.1	Q8N726-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000433 AC: 5 AN: 115386 AF XY: 0.0000474

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000564

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000778

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000656 AC: 89 AN: 1357220 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 35 AN XY: 668658

African (AFR) AF: 0.00 AC: 0 AN: 29172

American (AMR) AF: 0.000175 AC: 5 AN: 28558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21560

East Asian (EAS) AF: 0.00 AC: 0 AN: 35164

South Asian (SAS) AF: 0.00 AC: 0 AN: 73116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4200

European-Non Finnish (NFE) AF: 0.0000748 AC: 80 AN: 1069166

Other (OTH) AF: 0.0000711 AC: 4 AN: 56232

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000422 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
3	-	-	Melanoma-pancreatic cancer syndrome (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	CDKN2A-related disorder (1)
1	-	-	Familial melanoma (1)
1	-	-	Melanoma and neural system tumor syndrome (1)
1	-	-	Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome (1)
1	-	-	Melanoma, cutaneous malignant, susceptibility to, 2 (2)
1	-	-	Melanoma;C0919267:Ovarian neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.5
DANN	Benign	0.63
PhyloP100		-0.83
PromoterAI		-0.29	Neutral
Mutation Taster		=42/258	disease causing (ClinVar)

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: rs1800586; hg19: chr9-21974860; COSMIC: COSV58702359;