rs2069492

Variant names:

• chr14-99495493-T-C
• rs2069492
• NM_001099402.2:c.280-5T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001099402.2(CCNK):​c.280-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 1,603,206 control chromosomes in the GnomAD database, including 252,622 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19337 hom., cov: 32)
  • Exomes 𝑓: 0.56 (233285 hom.)
• Consequence: CCNK NM_001099402.2 splice_region, intron
• Scores: Splicing: ADA: 0.0008483
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.906
• Publications: 23 publications found

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: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 14-99495493-T-C is Benign according to our data. Variant chr14-99495493-T-C is described in ClinVar as Benign. ClinVar VariationId is 1192628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

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.280-5T>C		splice_region intron	N/A	NP_001092872.1	O75909-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCNK	ENST00000389879.9	TSL:5 MANE Select	c.280-5T>C		splice_region intron	N/A	ENSP00000374529.5	O75909-3
	CCNK	ENST00000555049.5	TSL:1	c.280-5T>C		splice_region intron	N/A	ENSP00000452307.1	G3V5E1
	CCNK	ENST00000553865.1	TSL:1	n.1524T>C		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.496 AC: 75365 AN: 151856 Hom.: 19336 Cov.: 32

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.518

GnomAD2 exomes AF: 0.503 AC: 120589 AN: 239596 AF XY: 0.517

Gnomad AFR exome AF: 0.385

Gnomad AMR exome AF: 0.352

Gnomad ASJ exome AF: 0.491

Gnomad EAS exome AF: 0.375

Gnomad FIN exome AF: 0.487

Gnomad NFE exome AF: 0.578

Gnomad OTH exome AF: 0.538

GnomAD4 exome AF: 0.563 AC: 816759 AN: 1451232 Hom.: 233285 Cov.: 34 AF XY: 0.563 AC XY: 406481 AN XY: 721942

African (AFR) AF: 0.385 AC: 12580 AN: 32704

American (AMR) AF: 0.366 AC: 15398 AN: 42082

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 12412 AN: 25780

East Asian (EAS) AF: 0.389 AC: 15408 AN: 39564

South Asian (SAS) AF: 0.528 AC: 44482 AN: 84298

European-Finnish (FIN) AF: 0.491 AC: 26123 AN: 53224

Middle Eastern (MID) AF: 0.567 AC: 3121 AN: 5502

European-Non Finnish (NFE) AF: 0.590 AC: 654202 AN: 1108202

Other (OTH) AF: 0.552 AC: 33033 AN: 59876

GnomAD4 genome AF: 0.496 AC: 75380 AN: 151974 Hom.: 19337 Cov.: 32 AF XY: 0.491 AC XY: 36439 AN XY: 74280

African (AFR) AF: 0.389 AC: 16130 AN: 41416

American (AMR) AF: 0.452 AC: 6900 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1638 AN: 3468

East Asian (EAS) AF: 0.366 AC: 1893 AN: 5172

South Asian (SAS) AF: 0.510 AC: 2453 AN: 4814

European-Finnish (FIN) AF: 0.493 AC: 5204 AN: 10548

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.579 AC: 39371 AN: 67962

Other (OTH) AF: 0.517 AC: 1093 AN: 2114

Alfa AF: 0.550 Hom.: 106608

Bravo AF: 0.486

Asia WGS AF: 0.479 AC: 1667 AN: 3478

EpiCase AF: 0.588

EpiControl AF: 0.593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CCNK-related disorder (1)
-	-	1	Intellectual developmental disorder with hypertelorism and distinctive facies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00085
dbscSNV1_RF	Benign	0.076
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: rs2069492; hg19: chr14-99961830; COSMIC: COSV66274819; COSMIC: COSV66274819;