dbSNP rs121913385: CDKN2A:p.His83Tyr (chr9-21971112-G-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

The NM_000077.5(CDKN2A):c.247C>T(p.His83Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. H83Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3O:1

Conservation

PhyloP100: 9.23

Publications

127 publications found

Variant links:

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

CDKN2A links:

ENSG00000264545 (HGNC:):

ENSG00000264545 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 48 uncertain in NM_000077.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-21971110-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 429110.

PP5

Variant 9-21971112-G-A is Pathogenic according to our data. Variant chr9-21971112-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376307.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000077.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKN2A	NM_000077.5	MANE Select	c.247C>T	p.His83Tyr	missense	Exon 2 of 3	NP_000068.1	P42771-1
CDKN2A	NM_058195.4	MANE Plus Clinical	c.290C>T	p.Ala97Val	missense	Exon 2 of 3	NP_478102.2	Q8N726-1
CDKN2A	NM_001195132.2		c.247C>T	p.His83Tyr	missense	Exon 2 of 4	NP_001182061.1	P42771-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.247C>T	p.His83Tyr	missense	Exon 2 of 3	ENSP00000307101.5	P42771-1
CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.290C>T	p.Ala97Val	missense	Exon 2 of 3	ENSP00000462950.1	Q8N726-1
CDKN2A	ENST00000498124.1	TSL:1	c.247C>T	p.His83Tyr	missense	Exon 2 of 4	ENSP00000418915.1	P42771-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

230846

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1451924

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722664

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44724

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5458

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111508

Other (OTH)

AF:

0.00

AC:

AN:

60248

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

Familial melanoma (1)

Melanoma and neural system tumor syndrome (1)

Melanoma-pancreatic cancer syndrome (1)

Embryonal rhabdomyosarcoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.47

MetaSVM

Uncertain

-0.20

PhyloP100

9.2

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.58

Sift

Benign

0.037

Sift4G

Benign

0.082

Vest4

0.44

MVP

1.0

ClinPred

0.92

GERP RS

5.9

PromoterAI

0.059

Neutral

(source)

Varity_R

0.70

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over