NM_058195.4:c.193+2215G>A

Variant names:

• chr9-21991924-C-T
• rs2811710
• NM_058195.4:c.193+2215G>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+2215G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 983,220 control chromosomes in the GnomAD database, including 77,739 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 0.46 (17719 hom., cov: 32)
  • Exomes 𝑓: 0.38 (60020 hom.)
• Consequence: CDKN2A NM_058195.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.85
• Publications: 25 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.193+2215G>A		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2
LOC124902130	XR_007061436.1	n.700G>A		non_coding_transcript_exon_variant	Exon 2 of 2
CDKN2A	NM_001363763.2	c.-4+2897G>A		intron_variant	Intron 1 of 2		NP_001350692.1
CDKN2A	XM_047422597.1	c.-4+2623G>A		intron_variant	Intron 1 of 2		XP_047278553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2	c.193+2215G>A		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70033 AN: 151832 Hom.: 17680 Cov.: 32

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.468

GnomAD4 exome AF: 0.377 AC: 313138 AN: 831270 Hom.: 60020 Cov.: 25 AF XY: 0.377 AC XY: 144835 AN XY: 383956

African (AFR) AF: 0.700 AC: 11017 AN: 15748

American (AMR) AF: 0.520 AC: 511 AN: 982

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 2069 AN: 5138

East Asian (EAS) AF: 0.318 AC: 1152 AN: 3620

South Asian (SAS) AF: 0.345 AC: 5664 AN: 16438

European-Finnish (FIN) AF: 0.341 AC: 94 AN: 276

Middle Eastern (MID) AF: 0.413 AC: 669 AN: 1618

European-Non Finnish (NFE) AF: 0.370 AC: 281413 AN: 760218

Other (OTH) AF: 0.387 AC: 10549 AN: 27232

GnomAD4 genome AF: 0.462 AC: 70141 AN: 151950 Hom.: 17719 Cov.: 32 AF XY: 0.459 AC XY: 34047 AN XY: 74248

African (AFR) AF: 0.676 AC: 28023 AN: 41442

American (AMR) AF: 0.506 AC: 7719 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1441 AN: 3468

East Asian (EAS) AF: 0.328 AC: 1695 AN: 5162

South Asian (SAS) AF: 0.337 AC: 1621 AN: 4806

European-Finnish (FIN) AF: 0.335 AC: 3534 AN: 10558

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24600 AN: 67928

Other (OTH) AF: 0.470 AC: 992 AN: 2112

Alfa AF: 0.393 Hom.: 5689

Bravo AF: 0.487

Asia WGS AF: 0.366 AC: 1269 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.11
DANN	Benign	0.33
PhyloP100		-3.9
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: rs2811710; hg19: chr9-21991923; COSMIC: COSV64266736; COSMIC: COSV64266736;