rs3731204

Variant names:

• chr9-21987585-T-C
• rs3731204
• NM_058195.4:c.193+6554A>G

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+6554A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 152,194 control chromosomes in the GnomAD database, including 1,114 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 0.11 (1114 hom., cov: 32)
• Consequence: CDKN2A NM_058195.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.552
• Publications: 13 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.193+6554A>G		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2
LOC124902130	XR_007061436.1	n.5039A>G		non_coding_transcript_exon_variant	Exon 2 of 2
CDKN2A	NM_001363763.2	c.-4+7236A>G		intron_variant	Intron 1 of 2		NP_001350692.1
CDKN2A	XM_047422597.1	c.-4+6962A>G		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+6554A>G		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17128 AN: 152076 Hom.: 1113 Cov.: 32

Gnomad AFR AF: 0.0949

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0349

Gnomad FIN AF: 0.0999

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.136

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

GnomAD4 genome AF: 0.113 AC: 17141 AN: 152194 Hom.: 1114 Cov.: 32 AF XY: 0.108 AC XY: 8051 AN XY: 74408

African (AFR) AF: 0.0948 AC: 3937 AN: 41538

American (AMR) AF: 0.105 AC: 1601 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 494 AN: 3466

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0346 AC: 167 AN: 4832

European-Finnish (FIN) AF: 0.0999 AC: 1058 AN: 10590

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9291 AN: 67976

Other (OTH) AF: 0.140 AC: 295 AN: 2112

Alfa AF: 0.124 Hom.: 153

Bravo AF: 0.116

Asia WGS AF: 0.0470 AC: 164 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.50
DANN	Benign	0.54
PhyloP100		-0.55
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: rs3731204; hg19: chr9-21987584;