chr14-99502748-T-G

Variant names:

• chr14-99502748-T-G
• NM_001099402.2:c.775T>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001099402.2(CCNK):​c.775T>G​(p.Ser259Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,400 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCNK NM_001099402.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52

Genes affected

CCNK (HGNC:1596): (cyclin K) The protein encoded by this gene is a member of the transcription cyclin family. These cyclins may regulate transcription through their association with and activation of cyclin-dependent kinases (CDK) that phosphorylate the C-terminal domain (CTD) of the large subunit of RNA polymerase II. This gene product may play a dual role in regulating CDK and RNA polymerase II activities. [provided by RefSeq, Jul 2008]

CCDC85C (HGNC:35459): (coiled-coil domain containing 85C) Predicted to be involved in cerebral cortex development. Located in adherens junction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCNK	NM_001099402.2	c.775T>G	p.Ser259Ala	missense_variant	Exon 8 of 11	ENST00000389879.9	NP_001092872.1
CCDC85C	NM_001144995.2	c.*12498A>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000380243.9	NP_001138467.1
CCNK	XM_005268154.5	c.775T>G	p.Ser259Ala	missense_variant	Exon 8 of 11		XP_005268211.1
CCNK	XM_047431839.1	c.775T>G	p.Ser259Ala	missense_variant	Exon 9 of 12		XP_047287795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCNK	ENST00000389879.9	c.775T>G	p.Ser259Ala	missense_variant	Exon 8 of 11	5	NM_001099402.2	ENSP00000374529.5
CCNK	ENST00000555049.5	c.775T>G	p.Ser259Ala	missense_variant	Exon 8 of 11	1		ENSP00000452307.1
CCDC85C	ENST00000380243	c.*12498A>C		3_prime_UTR_variant	Exon 6 of 6	5	NM_001144995.2	ENSP00000369592.4
CCNK	ENST00000553865.1	n.3301T>G		non_coding_transcript_exon_variant	Exon 3 of 5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461400 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726994

Gnomad4 AFR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.775T>G (p.S259A) alteration is located in exon 8 (coding exon 7) of the CCNK gene. This alteration results from a T to G substitution at nucleotide position 775, causing the serine (S) at amino acid position 259 to be replaced by an alanine (A). 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	0.091
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.12
Sift	Benign	0.058	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.0030	B;.
Vest4		0.70
MutPred		0.32		Gain of catalytic residue at L255 (P = 0.0155);Gain of catalytic residue at L255 (P = 0.0155);
MVP		0.66
MPC		1.2
ClinPred		0.72	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-99969085;