9-22006148-C-T

Position:

chr9-22006148-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_004936.4(CDKN2B):c.256G>A(p.Asp86Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00169 in 1,611,768 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 7 hom. )

Consequence

CDKN2B
NM_004936.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.36

Variant links:

Genes affected

CDKN2B (HGNC:1788): (cyclin dependent kinase inhibitor 2B) This gene lies adjacent to the tumor suppressor gene CDKN2A in a region that is frequently mutated and deleted in a wide variety of tumors. This gene encodes a cyclin-dependent kinase inhibitor, which forms a complex with CDK4 or CDK6, and prevents the activation of the CDK kinases, thus the encoded protein functions as a cell growth regulator that controls cell cycle G1 progression. The expression of this gene was found to be dramatically induced by TGF beta, which suggested its role in the TGF beta induced growth inhibition. Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported. [provided by RefSeq, Jul 2008]

CDKN2B links:

CDKN2B-AS1 (HGNC:34341): (CDKN2B antisense RNA 1) This gene is located within the CDKN2B-CDKN2A gene cluster at chromosome 9p21. The gene product is a functional RNA molecule that interacts with polycomb repressive complex-1 (PRC1) and -2 (PRC2), leading to epigenetic silencing of other genes in this cluster. This region is a significant genetic susceptibility locus for cardiovascular disease, and has also been linked to a number of other pathologies, including several cancers, intracranial aneurysm, type-2 diabetes, periodontitis, Alzheimer's disease, endometriosis, frailty in the elderly, and glaucoma. Multiple alternatively processed transcript variants have been detected, some of which may take the form of circular RNA molecules (PMID:21151960). [provided by RefSeq, May 2014]

CDKN2B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.119099796).

BP6

Variant 9-22006148-C-T is Benign according to our data. Variant chr9-22006148-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 426555.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS2

High AC in GnomAd4 at 176 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2B	NM_004936.4 linkuse as main transcript	c.256G>A	p.Asp86Asn	missense_variant	2/2	ENST00000276925.7
CDKN2B-AS1	NR_003529.3 linkuse as main transcript	n.371+10987C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2B	ENST00000276925.7 linkuse as main transcript	c.256G>A	p.Asp86Asn	missense_variant	2/2	1	NM_004936.4	P1	P42772-1
CDKN2B-AS1	ENST00000650946.1 linkuse as main transcript	n.29+10987C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

176

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00120

AC:

291

AN:

242194

Hom.:

AF XY:

0.00123

AC XY:

163

AN XY:

132258

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000466

Gnomad ASJ exome

AF:

0.00142

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.000655

Gnomad NFE exome

AF:

0.00216

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.00174

AC:

2542

AN:

1459390

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1241

AN XY:

726128

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.000583

Gnomad4 NFE exome

AF:

0.00213

Gnomad4 OTH exome

AF:

0.00126

GnomAD4 genome

AF:

0.00116

AC:

176

AN:

152378

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000240

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000470

Gnomad4 NFE

AF:

0.00207

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00195

Hom.:

Bravo

AF:

0.00117

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00303

AC:

ExAC

AF:

0.00142

AC:

172

EpiCase

AF:

0.00180

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CDKN2B: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2017	The D86N variant in the CDKN2B gene has been reported previously as a germline variant in one individual with a metastatic pancreatic endocrine tumor (Lindberg et al., 2008). The D86N variant has also been reported in an individual with primary hyperparathyroidism caused by a sporadic parathyroid adenoma; the D86N variant was present in the germline and accompanied by a loss of the second CDKN2B allele in the tumor sample (Costa-Guda et al., 2013). In addition, the D86N variant was reported as a germline variant in an individual with clear-cell renal cell carcinoma (Jafri et al., 2015). In vitro functional studies of the D86N variant demonstrate impaired CDK6 binding and impaired growth suppressor activity (Costa-Guda et al., 2013; Jafri et al., 2015). The D86N variant is observed in 150/61460 (0.24%) alleles from individuals of European background, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D86N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret D86N as a variant of uncertain significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.12

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

0.99

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.66

MVP

0.98

MPC

1.2

ClinPred

0.15

GERP RS

4.8

Varity_R

0.69

gMVP

0.78

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

Other links and lift over