9-21990458-C-T

Variant names:

• chr9-21990458-C-T
• rs7036656
• NM_058195.4:c.193+3681G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_058195.4(CDKN2A):​c.193+3681G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 151,822 control chromosomes in the GnomAD database, including 42,129 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (42129 hom., cov: 29)
• Consequence: CDKN2A NM_058195.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.186
• Publications: 21 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

LOC124902130 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058195.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.193+3681G>A		intron	N/A	NP_478102.2
	CDKN2A	NM_001363763.2		c.-4+4363G>A		intron	N/A	NP_001350692.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.193+3681G>A		intron	N/A	ENSP00000462950.1
	CDKN2A	ENST00000530628.2	TSL:5	c.193+3681G>A		intron	N/A	ENSP00000432664.2
	CDKN2A	ENST00000494262.5	TSL:3	c.-4+3424G>A		intron	N/A	ENSP00000464952.1

Frequencies

GnomAD3 genomes AF: 0.744 AC: 112928 AN: 151704 Hom.: 42111 Cov.: 29

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.835

Gnomad FIN AF: 0.766

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.726

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.744 AC: 113002 AN: 151822 Hom.: 42129 Cov.: 29 AF XY: 0.749 AC XY: 55553 AN XY: 74178

African (AFR) AF: 0.748 AC: 30930 AN: 41354

American (AMR) AF: 0.783 AC: 11955 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2403 AN: 3472

East Asian (EAS) AF: 0.784 AC: 4036 AN: 5146

South Asian (SAS) AF: 0.835 AC: 4017 AN: 4810

European-Finnish (FIN) AF: 0.766 AC: 8066 AN: 10526

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.726 AC: 49317 AN: 67942

Other (OTH) AF: 0.723 AC: 1522 AN: 2106

Alfa AF: 0.730 Hom.: 141262

Bravo AF: 0.742

Asia WGS AF: 0.805 AC: 2800 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.4
DANN	Benign	0.43
PhyloP100		-0.19
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

Other links and lift over

dbSNP: rs7036656; hg19: chr9-21990457;