rs4987127

Variant names:

• chr9-21971086-C-T
• rs4987127
• NM_058195.4:c.316G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-21971086-C-T
• chr9-21971086-C-A
• chr9-21971086-C-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The NM_058195.4(CDKN2A):​c.316G>A​(p.Gly106Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000729 in 1,605,320 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G106A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: CDKN2A NM_058195.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10 O:1
• Conservation: PhyloP100: 3.63
• Publications: 15 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 -9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 19 benign, 36 uncertain in NM_058195.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.14428085).
• BP6: Variant 9-21971086-C-T is Benign according to our data. Variant chr9-21971086-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133882.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00042 (64/152352) while in subpopulation AFR AF = 0.00142 (59/41590). AF 95% confidence interval is 0.00113. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 64 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.316G>A	p.Gly106Arg	missense	Exon 2 of 3	NP_478102.2	Q8N726-1
	CDKN2A	NM_000077.5	MANE Select	c.273G>A	p.Leu91Leu	synonymous	Exon 2 of 3	NP_000068.1	P42771-1
	CDKN2A	NM_001195132.2		c.273G>A	p.Leu91Leu	synonymous	Exon 2 of 4	NP_001182061.1	P42771-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.316G>A	p.Gly106Arg	missense	Exon 2 of 3	ENSP00000462950.1	Q8N726-1
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.273G>A	p.Leu91Leu	synonymous	Exon 2 of 3	ENSP00000307101.5	P42771-1
	CDKN2A	ENST00000498124.1	TSL:1	c.273G>A	p.Leu91Leu	synonymous	Exon 2 of 4	ENSP00000418915.1	P42771-4

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000469 AC: 11 AN: 234334 AF XY: 0.0000544

Gnomad AFR exome AF: 0.000546

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000944

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000365 AC: 53 AN: 1452968 Hom.: 0 Cov.: 31 AF XY: 0.0000387 AC XY: 28 AN XY: 723160

African (AFR) AF: 0.000897 AC: 30 AN: 33440

American (AMR) AF: 0.0000672 AC: 3 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45786

Middle Eastern (MID) AF: 0.000931 AC: 5 AN: 5372

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111536

Other (OTH) AF: 0.000116 AC: 7 AN: 60258

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74510

African (AFR) AF: 0.00142 AC: 59 AN: 41590

American (AMR) AF: 0.000261 AC: 4 AN: 15310

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: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000586 Hom.: 0

Bravo AF: 0.000465

ESP6500AA AF: 0.00138 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000750 AC: 9

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	1	2	not specified (4)
-	-	2	Melanoma-pancreatic cancer syndrome (2)
-	1	1	not provided (2)
-	-	1	CDKN2A-related disorder (1)
-	-	1	Familial melanoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.047	T
PhyloP100		3.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.68
Sift	Benign	0.21	T
Sift4G	Benign	0.23	T
Vest4		0.48
MVP		0.95
ClinPred		0.15	T
GERP RS		4.0
PromoterAI		-0.051	Neutral
Mutation Taster		=5/95	disease causing

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: rs4987127; hg19: chr9-21971085; COSMIC: COSV58729901;