chr9-21994134-C-T

Position:

• chr9-21994134-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_058195.4(CDKN2A):​c.193+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDKN2A NM_058195.4 splice_region, intron
• Scores: Splicing: ADA: 0.7621
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.21

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

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21994134-C-T is Pathogenic according to our data. Variant chr9-21994134-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.193+5G>A		splice_region_variant, intron_variant		ENST00000579755.2	NP_478102.2
CDKN2A	NM_001363763.2	c.-4+687G>A		intron_variant			NP_001350692.1
CDKN2A	XM_047422597.1	c.-4+413G>A		intron_variant			XP_047278553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2	c.193+5G>A		splice_region_variant, intron_variant		1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 18, 2022

Segregates with melanoma in many affected individuals from multiple families (Wadt 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 28830827, 25803691, 25294512) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2024

The c.193+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 1β in the CDKN2A (p14) gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations at +1 and +3 donor positions have been shown to have aberrant splicing (Harland M et al. Oncogene, 2005 Jun;24:4604-8). Among several other close match splice alterations at this same donor site, this alteration was identified in multiple familial melanoma kindreds (Harland M et al. Oncogene, 2005 Jun;24:4604-8). This alteration segregated strongly with melanoma in one family (Djursby M et al. Ugeskr. Laeg., 2014 Sep;176; Wadt KA et al. PLoS ONE, 2015 Mar;10:e0122662). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2021

This sequence change falls in intron 1 of the CDKN2A (p14ARF) gene. It does not directly change the encoded amino acid sequence of the CDKN2A (p14ARF) protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with multiple primary melanomas (PMID: 25294512, 25803691; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 141882). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.76
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.14		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: rs587782083; hg19: chr9-21994133; COSMIC: COSV64261578; COSMIC: COSV64261578;