rs3731249

Variant names:

• chr9-21970917-C-A
• rs3731249
• NM_000077.5:c.442G>T
• CDKN2A p.Ala148Ser

Your query was ambiguous. Multiple possible variants found:

• chr9-21970917-C-A
• chr9-21970917-C-G
• chr9-21970917-C-T

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000077.5(CDKN2A):c.442G>T (p.Ala148Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.A148= (synonymous): Likely_benign (ClinVar VariationId 921245, 2 stars); p.A148= (synonymous): Likely_benign (ClinVar VariationId 923208, 2 stars); p.A148P: Uncertain_significance (ClinVar VariationId 483343, 2 stars); p.A148T: Benign (ClinVar VariationId 41580, 2 stars); p.A148V: Uncertain_significance (ClinVar VariationId 231700, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.153
• Publications: 137 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: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, 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

ENSG00000264545 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (base 0.0001, raised to 0.00011 by highest known P/LP ClinVar AF 0.00011) — PM2 moderate.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CDKN2A NM_000077.5	MANE Select	c.442G>T p.Ala148Ser	missense	Exon 2 of 3	Prot: NP_000068.1 UniProt:
	CDKN2A NM_058195.4	MANE Plus Clinical	c.*86G>T	3_prime_UTR	Exon 2 of 3	Prot: NP_478102.2 UniProt:
	CDKN2A NM_001195132.2		c.442G>T p.Ala148Ser	missense	Exon 2 of 4	Prot: NP_001182061.1 UniProt:

CDKN2A NM_000077.5

MANE Select

HGVSc / HGVSpc.442G>Tp.Ala148Ser

Exon rankExon 2 of 3

missense

Prot: NP_000068.1UniProt: K7PML8P42771-1

CDKN2A NM_058195.4

MANE Plus Clinical

HGVSc / HGVSpc.*86G>T

Exon rankExon 2 of 3

3_prime_UTR

Prot: NP_478102.2UniProt: Q8N726-1

CDKN2A NM_001195132.2

HGVSc / HGVSpc.442G>Tp.Ala148Ser

Exon rankExon 2 of 4

missense

Prot: NP_001182061.1UniProt: P42771-4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CDKN2A ENST00000304494.10	TSL:1MANE Select	c.442G>T p.Ala148Ser	missense	Exon 2 of 3	Prot: ENSP00000307101.5 UniProt:
	CDKN2A ENST00000498124.1	TSL:1	c.442G>T p.Ala148Ser	missense	Exon 2 of 4	Prot: ENSP00000418915.1 UniProt:
	CDKN2A ENST00000579755.2	TSL:1MANE Plus Clinical	c.*86G>T	3_prime_UTR	Exon 2 of 3	Prot: ENSP00000462950.1 UniProt:

CDKN2A ENST00000304494.10

TSL:1MANE Select

HGVSc / HGVSpc.442G>Tp.Ala148Ser

Exon rankExon 2 of 3

missense

Prot: ENSP00000307101.5UniProt: P42771-1

CDKN2A ENST00000498124.1

TSL:1

HGVSc / HGVSpc.442G>Tp.Ala148Ser

Exon rankExon 2 of 4

missense

Prot: ENSP00000418915.1UniProt: P42771-4

CDKN2A ENST00000579755.2

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.*86G>T

Exon rankExon 2 of 3

3_prime_UTR

Prot: ENSP00000462950.1UniProt: Q8N726-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:315	AN:706520	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial melanoma (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	8.5
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	0.0038	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	10
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
FuncVEP CTI	Benign	0.10
GPN-Star LLR	N/A	-0.48
GPN-Star score	N/A	0.48
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.97	T
Mutation Taster	N/A	51/49	polymorphism
PhyloP100	Benign	0.15
popEVE	Benign	-2.8
PrimateAI	Benign	0.39	T
PromoterAI	N/A	-0.0061	Neutral
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.097	T
Varity_R	N/A	0.11
VESM-3B	Benign	-3.1

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3731249;

hg19: chr9-21970916;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar