Genetic Variant NM_001099402.2:c.331A>G (chr14-99495549-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP3PP5

The NM_001099402.2(CCNK):c.331A>G(p.Lys111Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

CCNK
NM_001099402.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.14

Publications

0 publications found

Variant links:

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]

CCNK Gene-Disease associations (from GenCC):

intellectual developmental disorder with hypertelorism and distinctive facies
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

CCNK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.305 (above the threshold of 3.09). Trascript score misZ: 1.9964 (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder with hypertelorism and distinctive facies.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.814

PP5

Variant 14-99495549-A-G is Pathogenic according to our data. Variant chr14-99495549-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 585310.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099402.2. 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
	CCNK	NM_001099402.2	MANE Select	c.331A>G	p.Lys111Glu	missense	Exon 4 of 11	NP_001092872.1	O75909-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCNK	ENST00000389879.9	TSL:5 MANE Select	c.331A>G	p.Lys111Glu	missense	Exon 4 of 11	ENSP00000374529.5	O75909-3
CCNK	ENST00000555049.5	TSL:1	c.331A>G	p.Lys111Glu	missense	Exon 4 of 11	ENSP00000452307.1	G3V5E1
CCNK	ENST00000553865.1	TSL:1	n.1580A>G		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual developmental disorder with hypertelorism and distinctive facies (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.049

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.72

MutationAssessor

Pathogenic

3.8

PhyloP100

9.1

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.86

MutPred

0.59

Loss of methylation at K111 (P = 0.0173)

MVP

0.81

MPC

3.2

ClinPred

1.0

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.94

gMVP

0.97

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over