rs529380972

Variant names:

• chr9-21971212-C-G
• rs529380972
• NM_000077.5:c.151-4G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000077.5(CDKN2A):​c.151-4G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000919 in 1,596,954 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (29 hom.)
• Consequence: CDKN2A NM_000077.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001552
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -0.120
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 9-21971212-C-G is Benign according to our data. Variant chr9-21971212-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141600.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000538 (82/152316) while in subpopulation SAS AF = 0.0168 (81/4828). AF 95% confidence interval is 0.0138. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 82 AD gene.

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.151-4G>C		splice_region intron	N/A	NP_000068.1	P42771-1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.194-4G>C		splice_region intron	N/A	NP_478102.2	Q8N726-1
	CDKN2A	NM_001195132.2		c.151-4G>C		splice_region intron	N/A	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.151-4G>C		splice_region intron	N/A	ENSP00000307101.5	P42771-1
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.194-4G>C		splice_region intron	N/A	ENSP00000462950.1	Q8N726-1
	CDKN2A	ENST00000498124.1	TSL:1	c.151-4G>C		splice_region intron	N/A	ENSP00000418915.1	P42771-4

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152196 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: 0.0168

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00200 AC: 439 AN: 219288 AF XY: 0.00257

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000304

Gnomad OTH exome AF: 0.000358

GnomAD4 exome AF: 0.000959 AC: 1386 AN: 1444638 Hom.: 29 Cov.: 31 AF XY: 0.00137 AC XY: 985 AN XY: 719038

African (AFR) AF: 0.0000300 AC: 1 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.0152 AC: 1307 AN: 85878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38492

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5744

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110864

Other (OTH) AF: 0.00116 AC: 70 AN: 60144

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000831

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.7
DANN	Benign	0.77
PhyloP100		-0.12
PromoterAI		0.017	Neutral
Mutation Taster		=297/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs529380972; hg19: chr9-21971211; COSMIC: COSV58723120;