rs2811708

Variant names:

• chr9-21973423-G-A
• rs2811708
• NM_000077.5:c.150+1255C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-21973423-G-A
• chr9-21973423-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000077.5(CDKN2A):​c.150+1255C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 151,922 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 Benign (★).

• Frequency: Genomes: 𝑓 0.00035 (0 hom., cov: 32)
• Consequence: CDKN2A NM_000077.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.892

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]

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 9-21973423-G-A is Benign according to our data. Variant chr9-21973423-G-A is described in ClinVar as [Benign]. Clinvar id is 2573227.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000349 (53/151922) while in subpopulation SAS AF = 0.00249 (12/4816). AF 95% confidence interval is 0.00144. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.150+1255C>T		intron_variant	Intron 1 of 2	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-2215C>T		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.150+1255C>T		intron_variant	Intron 1 of 2	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.194-2215C>T		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 151804 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000481

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

GnomAD4 genome AF: 0.000349 AC: 53 AN: 151922 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74226

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241383 AN: 0.0000241383

Gnomad4 AMR AF: 0.000131 AC: 0.000130907 AN: 0.000130907

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00249 AC: 0.00249169 AN: 0.00249169

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000545 AC: 0.000544518 AN: 0.000544518

Gnomad4 OTH AF: 0.000476 AC: 0.000475737 AN: 0.000475737

Alfa AF: 0.0000513 Hom.: 4295

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Melanoma-pancreatic cancer syndrome Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.2
DANN	Benign	0.89
Mutation Taster		=100/0	polymorphism

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

Publications

LitVar

Other links and lift over

dbSNP: rs2811708; hg19: chr9-21973422;