chr19-10568596-C-T

Variant names:

• chr19-10568596-C-T
• rs1242536588
• NM_001800.4:c.58G>A

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.58G>A​(p.Asp20Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000532 in 1,505,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: CDKN2D NM_001800.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08
• 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=0.20473585).

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.58G>A	p.Asp20Asn	missense	Exon 1 of 2	NP_001791.1	P55273
	CDKN2D	NM_079421.3		c.58G>A	p.Asp20Asn	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.58G>A	p.Asp20Asn	missense	Exon 1 of 2	ENSP00000377224.1	P55273
	CDKN2D	ENST00000335766.2	TSL:1	c.58G>A	p.Asp20Asn	missense	Exon 2 of 3	ENSP00000337056.1	P55273

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000517 AC: 7 AN: 1352836 Hom.: 0 Cov.: 33 AF XY: 0.00000895 AC XY: 6 AN XY: 670160

African (AFR) AF: 0.00 AC: 0 AN: 28200

American (AMR) AF: 0.00 AC: 0 AN: 33390

Ashkenazi Jewish (ASJ) AF: 0.0000851 AC: 2 AN: 23510

East Asian (EAS) AF: 0.00 AC: 0 AN: 31068

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 76016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5076

European-Non Finnish (NFE) AF: 0.00000376 AC: 4 AN: 1065100

Other (OTH) AF: 0.00 AC: 0 AN: 55708

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.1
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.11
Sift	Benign	0.26	T
Sift4G	Benign	0.31	T
Polyphen		0.25	B
Vest4		0.10
MutPred		0.46		Gain of MoRF binding (P = 0.0394)
MVP		0.77
MPC		0.48
ClinPred		0.69	D
GERP RS		4.1
PromoterAI		-0.087	Neutral
Varity_R		0.28
gMVP		0.33
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs1242536588; hg19: chr19-10679272;