9-127789170-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001261.4(CDK9):c.754-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00464 in 1,554,136 control chromosomes in the GnomAD database, including 14 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (14 hom.)
• Consequence: CDK9 NM_001261.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006251
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.933

Genes affected

CDK9 (HGNC:1780): (cyclin dependent kinase 9) The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, and known as important cell cycle regulators. This kinase was found to be a component of the multiprotein complex TAK/P-TEFb, which is an elongation factor for RNA polymerase II-directed transcription and functions by phosphorylating the C-terminal domain of the largest subunit of RNA polymerase II. This protein forms a complex with and is regulated by its regulatory subunit cyclin T or cyclin K. HIV-1 Tat protein was found to interact with this protein and cyclin T, which suggested a possible involvement of this protein in AIDS. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 9-127789170-C-T is Benign according to our data. Variant chr9-127789170-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3037641.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 449 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK9	NM_001261.4	c.754-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000373264.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK9	ENST00000373264.5	c.754-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001261.4	P1
CDK9	ENST00000498339.1	n.272-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 449 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00485

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00328 AC: 700 AN: 213244 Hom.: 1 AF XY: 0.00323 AC XY: 369 AN XY: 114256

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.000618

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000977

Gnomad FIN exome AF: 0.00444

Gnomad NFE exome AF: 0.00524

Gnomad OTH exome AF: 0.00335

GnomAD4 exome AF: 0.00482 AC: 6761 AN: 1401866 Hom.: 14 Cov.: 31 AF XY: 0.00453 AC XY: 3124 AN XY: 689820

Gnomad4 AFR exome AF: 0.000915

Gnomad4 AMR exome AF: 0.00129

Gnomad4 ASJ exome AF: 0.000662

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.000883

Gnomad4 FIN exome AF: 0.00471

Gnomad4 NFE exome AF: 0.00567

Gnomad4 OTH exome AF: 0.00403

GnomAD4 genome AF: 0.00294 AC: 448 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.00275 AC XY: 205 AN XY: 74460

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00485

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00359 Hom.: 2

Bravo AF: 0.00237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CDK9-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	1.0
Dann	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000063
dbscSNV1_RF	Benign	0.0
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

LitVar

Other links and lift over

dbSNP: rs3217748; hg19: chr9-130551449;