rs181044510

Variant names:

• chr9-21968733-G-A
• rs181044510
• ENST00000498124.1:c.496C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-21968733-G-A
• chr9-21968733-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001195132.2(CDKN2A):​c.496C>T​(p.His166Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000933 in 1,536,164 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (11 hom.)
• Consequence: CDKN2A NM_001195132.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:1
• Conservation: PhyloP100: -0.385
• Publications: 11 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), Genomics England PanelApp, ClinGen, 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:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018141866).
• BP6: Variant 9-21968733-G-A is Benign according to our data. Variant chr9-21968733-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133880.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00217 (330/152338) while in subpopulation EAS AF = 0.0027 (14/5176). AF 95% confidence interval is 0.00164. There are 3 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 330 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195132.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	NM_000077.5	MANE Select	c.458-491C>T		intron	N/A	NP_000068.1	P42771-1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.*102-491C>T		intron	N/A	NP_478102.2	Q8N726-1
	CDKN2A	NM_001195132.2		c.496C>T	p.His166Tyr	missense	Exon 3 of 4	NP_001182061.1	P42771-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000498124.1	TSL:1	c.496C>T	p.His166Tyr	missense	Exon 3 of 4	ENSP00000418915.1	P42771-4
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.458-491C>T		intron	N/A	ENSP00000307101.5	P42771-1
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.*102-491C>T		intron	N/A	ENSP00000462950.1	Q8N726-1

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 329 AN: 152220 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00138 AC: 186 AN: 134580 AF XY: 0.00124

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00181

Gnomad FIN exome AF: 0.0271

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.000724

GnomAD4 exome AF: 0.000798 AC: 1104 AN: 1383826 Hom.: 11 Cov.: 32 AF XY: 0.000773 AC XY: 528 AN XY: 682858

African (AFR) AF: 0.0000317 AC: 1 AN: 31594

American (AMR) AF: 0.00 AC: 0 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25182

East Asian (EAS) AF: 0.00148 AC: 53 AN: 35728

South Asian (SAS) AF: 0.0000505 AC: 4 AN: 79236

European-Finnish (FIN) AF: 0.0236 AC: 800 AN: 33894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.000165 AC: 178 AN: 1078884

Other (OTH) AF: 0.00116 AC: 67 AN: 57912

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152338 Hom.: 3 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0271 AC: 288 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000933 Hom.: 0

Bravo AF: 0.000317

ExAC AF: 0.000279 AC: 5

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Melanoma-pancreatic cancer syndrome (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.3
DANN	Benign	0.85
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.83	T
PhyloP100		-0.39
PROVEAN	Benign	-0.030	N
Sift	Benign	0.077	T
Vest4		0.15
MVP		0.94
MPC		0.45
ClinPred		0.0092	T
GERP RS		-5.6
gMVP		0.41
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs181044510; hg19: chr9-21968732; COSMIC: COSV105891472; COSMIC: COSV105891472;