9-21974860-C-G

Variant names:

• chr9-21974860-C-G
• rs531597737
• ENST00000498124.1:c.-33G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000498124.1(CDKN2A):​c.-33G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,515,778 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: CDKN2A ENST00000498124.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.08
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-21974860-C-G is Benign according to our data. Variant chr9-21974860-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 548857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00127 (193/152310) while in subpopulation NFE AF = 0.00219 (149/68026). AF 95% confidence interval is 0.0019. There are 1 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 193 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.194-3652G>C		intron	N/A	NP_478102.2	Q8N726-1
	CDKN2A	NM_001363763.2		c.-3-3652G>C		intron	N/A	NP_001350692.1	P42771-2
	CDKN2A	NM_000077.5	MANE Select	c.-33G>C		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.-33G>C		5_prime_UTR	Exon 1 of 4	ENSP00000418915.1	P42771-4
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.194-3652G>C		intron	N/A	ENSP00000462950.1	Q8N726-1
	CDKN2A	ENST00000530628.2	TSL:5	c.194-3652G>C		intron	N/A	ENSP00000432664.2	Q8N726-1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00119 AC: 146 AN: 122584 AF XY: 0.00119

Gnomad AFR exome AF: 0.000316

Gnomad AMR exome AF: 0.000475

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00170

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00149 AC: 2034 AN: 1363468 Hom.: 4 Cov.: 31 AF XY: 0.00151 AC XY: 1012 AN XY: 672112

African (AFR) AF: 0.000237 AC: 7 AN: 29484

American (AMR) AF: 0.000437 AC: 13 AN: 29724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21922

East Asian (EAS) AF: 0.000282 AC: 10 AN: 35416

South Asian (SAS) AF: 0.000378 AC: 28 AN: 74064

European-Finnish (FIN) AF: 0.00183 AC: 74 AN: 40346

Middle Eastern (MID) AF: 0.000940 AC: 4 AN: 4254

European-Non Finnish (NFE) AF: 0.00172 AC: 1840 AN: 1071728

Other (OTH) AF: 0.00103 AC: 58 AN: 56530

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74476

African (AFR) AF: 0.000120 AC: 5 AN: 41570

American (AMR) AF: 0.000261 AC: 4 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00219 AC: 149 AN: 68026

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.00122

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	2	Melanoma-pancreatic cancer syndrome (2)
-	-	1	Familial melanoma (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.085
DANN	Benign	0.40
PhyloP100		-3.1
PromoterAI		-0.20	Neutral
Mutation Taster		=299/1	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: rs531597737; hg19: chr9-21974859;