19-10568644-C-G

Variant names:

• chr19-10568644-C-G
• rs765253798
• NM_001800.4:c.10G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001800.4(CDKN2D):​c.10G>C​(p.Glu4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,344,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E4K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CDKN2D NM_001800.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.683
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09903315).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001800.4. 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
	CDKN2D	NM_001800.4	MANE Select	c.10G>C	p.Glu4Gln	missense	Exon 1 of 2	NP_001791.1	P55273
	CDKN2D	NM_079421.3		c.10G>C	p.Glu4Gln	missense	Exon 2 of 3	NP_524145.1	P55273

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2D	ENST00000393599.3	TSL:1 MANE Select	c.10G>C	p.Glu4Gln	missense	Exon 1 of 2	ENSP00000377224.1	P55273
	CDKN2D	ENST00000335766.2	TSL:1	c.10G>C	p.Glu4Gln	missense	Exon 2 of 3	ENSP00000337056.1	P55273

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1344452 Hom.: 0 Cov.: 32 AF XY: 0.00000150 AC XY: 1 AN XY: 666552

African (AFR) AF: 0.0000714 AC: 2 AN: 28030

American (AMR) AF: 0.00 AC: 0 AN: 32016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23020

East Asian (EAS) AF: 0.00 AC: 0 AN: 31048

South Asian (SAS) AF: 0.00 AC: 0 AN: 74864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1060990

Other (OTH) AF: 0.00 AC: 0 AN: 55152

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.68
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.093
Sift	Benign	0.16	T
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.053
MutPred		0.29		Gain of MoRF binding (P = 0.0025)
MVP		0.84
MPC		0.48
ClinPred		0.12	T
GERP RS		3.6
PromoterAI		-0.072	Neutral
Varity_R		0.084
gMVP		0.51
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs765253798; hg19: chr19-10679320;