Variant 19-10568587-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001800.4(CDKN2D):c.67G>C(p.Glu23Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000955 in 1,507,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

CDKN2D
NM_001800.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.13

Variant links:

Genes affected

CDKN2D (HGNC:1790): (cyclin dependent kinase inhibitor 2D) The protein encoded by this gene is a member of the INK4 family of cyclin-dependent kinase inhibitors. This protein has been shown to form a stable complex with CDK4 or CDK6, and prevent the activation of the CDK kinases, thus function as a cell growth regulator that controls cell cycle G1 progression. The abundance of the transcript of this gene was found to oscillate in a cell-cycle dependent manner with the lowest expression at mid G1 and a maximal expression during S phase. The negative regulation of the cell cycle involved in this protein was shown to participate in repressing neuronal proliferation, as well as spermatogenesis. Two alternatively spliced variants of this gene, which encode an identical protein, have been reported. [provided by RefSeq, Jul 2008]

CDKN2D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29462785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2D	NM_001800.4 linkuse as main transcript	c.67G>C	p.Glu23Gln	missense_variant	1/2	ENST00000393599.3	NP_001791.1	P55273A0A024R796
CDKN2D	NM_079421.3 linkuse as main transcript	c.67G>C	p.Glu23Gln	missense_variant	2/3		NP_524145.1	P55273A0A024R796

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2D	ENST00000393599.3 linkuse as main transcript	c.67G>C	p.Glu23Gln	missense_variant	1/2	1	NM_001800.4	ENSP00000377224.1		P55273
CDKN2D	ENST00000335766.2 linkuse as main transcript	c.67G>C	p.Glu23Gln	missense_variant	2/3	1		ENSP00000337056.1		P55273

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000230

AC:

AN:

130372

Hom.:

AF XY:

0.0000401

AC XY:

AN XY:

74772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000521

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000989

AC:

134

AN:

1354934

Hom.:

Cov.:

AF XY:

0.0000968

AC XY:

AN XY:

671332

show subpopulations

Gnomad4 AFR exome

AF:

0.0000354

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:

0.000123

Gnomad4 OTH exome

AF:

0.0000358

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.0000267

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.67G>C (p.E23Q) alteration is located in exon 1 (coding exon 1) of the CDKN2D gene. This alteration results from a G to C substitution at nucleotide position 67, causing the glutamic acid (E) at amino acid position 23 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.73

.;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.8

L;L

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.68

N;N

REVEL

Benign

0.17

Sift

Benign

0.39

T;T

Sift4G

Benign

0.31

T;T

Polyphen

1.0

D;D

Vest4

0.25

MVP

0.82

MPC

0.51

ClinPred

0.38

GERP RS

3.0

Varity_R

0.41

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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