Genetic Variant CDKN2AIP:p.Leu88Leu (chr4-183445061-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_017632.4(CDKN2AIP):c.264C>T(p.Leu88Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000379 in 1,582,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

CDKN2AIP
NM_017632.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.640

Publications

1 publications found

Variant links:

Genes affected

CDKN2AIP (HGNC:24325): (CDKN2A interacting protein) The protein encoded by this gene regulates the DNA damage response through several different signaling pathways. One such pathway is the p53-HDM2-p21(WAF1) pathway, which is critical to the DNA damage response. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

CDKN2AIP links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 4-183445061-C-T is Benign according to our data. Variant chr4-183445061-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2655205.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.64 with no splicing effect.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017632.4. 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
	CDKN2AIP	NM_017632.4	MANE Select	c.264C>T	p.Leu88Leu	synonymous	Exon 1 of 3	NP_060102.1	Q9NXV6
	CDKN2AIP	NM_001317343.2		c.264C>T	p.Leu88Leu	synonymous	Exon 1 of 3	NP_001304272.1	J3KNE1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDKN2AIP	ENST00000504169.2	TSL:1 MANE Select	c.264C>T	p.Leu88Leu	synonymous	Exon 1 of 3	ENSP00000427108.1	Q9NXV6
CDKN2AIP	ENST00000855690.1		c.264C>T	p.Leu88Leu	synonymous	Exon 1 of 3	ENSP00000525749.1
CDKN2AIP	ENST00000510928.1	TSL:2	c.264C>T	p.Leu88Leu	synonymous	Exon 1 of 2	ENSP00000421308.1	D6RGD2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD2 exomes

AF:

0.0000249

AC:

AN:

240870

AF XY:

0.0000153

show subpopulations

Gnomad AFR exome

AF:

0.0000635

Gnomad AMR exome

AF:

0.0000905

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000350

AC:

AN:

1430448

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

705112

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32630

American (AMR)

AF:

0.0000460

AC:

AN:

43486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25458

East Asian (EAS)

AF:

0.00

AC:

AN:

38668

South Asian (SAS)

AF:

0.00

AC:

AN:

84754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1088668

Other (OTH)

AF:

0.0000170

AC:

AN:

58836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

8.3

(source)

DANN

Benign

0.95

PhyloP100

-0.64

PromoterAI

-0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over