10-60785677-C-A

Variant names:

• chr10-60785677-C-A
• rs780626115
• NM_001786.5:c.208C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001786.5(CDK1):​c.208C>A​(p.Leu70Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. L70V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDK1 NM_001786.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.87
• Publications: 0 publications found

Genes affected

CDK1 (HGNC:1722): (cyclin dependent kinase 1) The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is a catalytic subunit of the highly conserved protein kinase complex known as M-phase promoting factor (MPF), which is essential for G2/M phase transitions of eukaryotic cell cycle. Mitotic cyclins stably associate with this protein and function as regulatory subunits. The kinase activity of this protein is controlled by cyclin accumulation and destruction through the cell cycle. The phosphorylation and dephosphorylation of this protein also play important regulatory roles in cell cycle control. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2023]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40143186).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001786.5. 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
	CDK1	NM_001786.5	MANE Select	c.208C>A	p.Leu70Ile	missense	Exon 4 of 8	NP_001777.1	P06493-1
	CDK1	NM_001320918.1		c.208C>A	p.Leu70Ile	missense	Exon 4 of 8	NP_001307847.1	P06493-1
	CDK1	NM_033379.5		c.208C>A	p.Leu70Ile	missense	Exon 4 of 7	NP_203698.1	P06493-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK1	ENST00000395284.8	TSL:1 MANE Select	c.208C>A	p.Leu70Ile	missense	Exon 4 of 8	ENSP00000378699.3	P06493-1
	CDK1	ENST00000448257.6	TSL:1	c.208C>A	p.Leu70Ile	missense	Exon 4 of 8	ENSP00000397973.2	A0A024QZP7
	CDK1	ENST00000373809.2	TSL:1	c.208C>A	p.Leu70Ile	missense	Exon 3 of 6	ENSP00000362915.2	P06493-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450590 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 721592

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33136

American (AMR) AF: 0.00 AC: 0 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25882

East Asian (EAS) AF: 0.00 AC: 0 AN: 39516

South Asian (SAS) AF: 0.00 AC: 0 AN: 84236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104872

Other (OTH) AF: 0.00 AC: 0 AN: 59870

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.11	N
PhyloP100		7.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.10	N
REVEL	Uncertain	0.29
Sift	Benign	0.81	T
Sift4G	Benign	1.0	T
Polyphen		0.058	B
Vest4		0.63
MutPred		0.41		Gain of sheet (P = 0.0827)
MVP		0.70
MPC		1.3
ClinPred		0.95	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.34
Mutation Taster		=33/67	disease causing

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: rs780626115; hg19: chr10-62545435;