chr9-21971147-T-C

Position:

chr9-21971147-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_000077.5(CDKN2A):c.212A>G(p.Asn71Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000376 in 1,593,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N71K) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.41

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 links:

CDKN2A (HGNC:):

CDKN2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a repeat ANK 2 (size 28) in uniprot entity CDN2A_HUMAN there are 15 pathogenic changes around while only 3 benign (83%) in NM_000077.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

PP5

Variant 9-21971147-T-C is Pathogenic according to our data. Variant chr9-21971147-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5 linkuse as main transcript	c.212A>G	p.Asn71Ser	missense_variant	2/3	ENST00000304494.10	NP_000068.1	P42771-1K7PML8
CDKN2A	NM_058195.4 linkuse as main transcript	c.255A>G	p.Gln85Gln	synonymous_variant	2/3	ENST00000579755.2	NP_478102.2	Q8N726-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10 linkuse as main transcript	c.212A>G	p.Asn71Ser	missense_variant	2/3	1	NM_000077.5	ENSP00000307101.5		P42771-1
CDKN2A	ENST00000579755.2 linkuse as main transcript	c.255A>G	p.Gln85Gln	synonymous_variant	2/3	1	NM_058195.4	ENSP00000462950.1		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000473

AC:

AN:

211414

Hom.:

AF XY:

0.00

AC XY:

AN XY:

117768

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000303

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000347

AC:

AN:

1441448

Hom.:

Cov.:

AF XY:

0.00000558

AC XY:

AN XY:

717046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000271

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000840

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 21, 2023	The p.N71S variant (also known as c.212A>G), located in coding exon 2 of the CDKN2A gene, results from an A to G substitution at nucleotide position 212. The asparagine at codon 71 is replaced by serine, an amino acid with highly similar properties. This variant has been reported in familial melanoma families and has been noted to segregate with disease, although unaffected individuals have also been reported to carry the variant (Della Torre G et al. Br. J. Cancer, 2001 Sep;85:836-44; Goldstein AM et al. Cancer Epidemiol. Biomarkers Prev. 2000 Sep; 9(9):889-94, Hussussian CJ et al. Nat. Genet. 1994 Sep; 8(1):15-21). Multiple functional studies have studied the ability of this variant to bind to CDK4 and CDK6 substrates, localize properly in the cell, and perform cell cycle inhibition (Ranade K et al. Nat. Genet. 1995 May; 10(1):114-6, Walker GJ et al. Int. J. Cancer 1999 Jul;82(2):305-12, Yarbrough WG et al. J. Natl. Cancer Inst. 1999 Sep; 91(18):1569-74, McKenzie HA et al. Hum. Mutat. 2010 Jun; 31(6):692-701; Miller PJ et al. Hum. Mutat. 2011 Aug; 32(8):900-11). CDK4 and CDK6 binding ability was reportedly at least partially retained in all but one study (Miller et al. 2011), which reported complete loss of CDK4 binding ability. In both Walker et al. and Yarbrough et al., this variant demonstrated abnormal localization of the protein within the cell nucleus. Across all studies, this variant also demonstrated significantly diminished ability to inhibit cell proliferation or perform cell cycle arrest. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 01, 2020	This missense variant replaces asparagine with serine at codon 71 of the CDKN2A (p16INK4A) protein. This variant has been reported in over ten individuals and families affected with melanoma (PMID: 7987387, 21462282, 10861313, 12072543, 11556834, 18363633, 22841127, 10390011). This variant has been identified in 1/211414 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant disrupts the protein function in regulating cell cycle arrest and cell proliferation (PMID: 7566978, 7647780, 10389768, 10491434, 10498896, 21462282). The variant impact on CDKN2A (p16INK4a) binding to CDK4 and CDK6 is inconsistent (PMID: 7566978, 10389768, 10491434, 10498896, 19260062, 20340136, 21462282). However, this binding activity showed a poor correlation with cell cycle control function and clinical relevance (PMID: 21462282). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Feb 23, 2022	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2014

This variant is denoted CDKN2A c.212A>G at the cDNA level, p.Asn71Ser (N71S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant was observed in multiple families with personal and family histories consistent with familial atypical multiple mole melanoma (FAMMM) syndrome (Della Torre 2001, Bishop 2002, Mantelli 2002, Goldstein 2007). CDKN2A Asn71Ser was found to bind CDK4 and CDK6 similarly to wild type by co-immunoprecipitation assay (Walker 1999, Yarbrough 1999). However, a two-hybrid assay indicated reduced binding to both CDK4 and CDK6 (McKenzie 2010). Yarbrough (1999) also found that CDKN2A exhibited intact inhibition of CDK6 and CDK-activating complex activities by in vitro kinase inhibition assay. However; CDKN2A Asn71Ser showed reduced ability to inhibit cell growth and to induce cell-cycle arrest (Walker 1999, Yarbrough 1999). A Bayesian analysis using functional, segregation and in silico data predicted CDKN2A Asn71Ser to be pathogenic (Miller 2011). CDKN2A Asn71Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. CDKN2A Asn71Ser occurs at a position that is highly conserved in mammals and is located in AK2 repeat (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider CDKN2A Asn71Ser to be a likely pathogenic variant. -

Familial melanoma

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 71 of the CDKN2A (p16INK4a) protein (p.Asn71Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with melanoma (PMID: 7987387, 10390011, 10861313, 11556834, 12072543, 18363633, 21462282, 22841127). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asn63Ser. ClinVar contains an entry for this variant (Variation ID: 418121). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 7566978, 7647780, 10389768, 10491434, 10498896, 19260062, 20340136, 21462282). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;T;.;.;.;.;T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;.;D;.;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.89

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.50

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.5

D;.;.;D;.;.;.;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.013

D;.;.;D;.;.;.;.

Sift4G

Uncertain

0.024

D;T;D;D;D;D;D;D

Polyphen

0.99

D;.;.;.;.;.;.;.

Vest4

0.67

MutPred

0.74

Gain of glycosylation at N71 (P = 0.0266);Gain of glycosylation at N71 (P = 0.0266);.;Gain of glycosylation at N71 (P = 0.0266);.;.;.;.;

MVP

0.94

MPC

0.83

ClinPred

0.92

GERP RS

5.8

Varity_R

0.30

gMVP

0.74

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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