9-127788208-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001261.4(CDK9):c.433-6C>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 0.00909 in 1,613,898 control chromosomes in the GnomAD database, including 1,145 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 0.047 (585 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (560 hom.)
• Consequence: CDK9 NM_001261.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001668
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.429

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-127788208-C-T is Benign according to our data. Variant chr9-127788208-C-T is described in ClinVar as [Benign]. Clinvar id is 3055715.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK9	NM_001261.4	c.433-6C>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.433-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001261.4	P1
CDK9	ENST00000480353.5	n.508-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2
CDK9	ENST00000491521.1	n.277-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0464 AC: 7066 AN: 152218 Hom.: 582 Cov.: 33

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.0321

GnomAD3 exomes AF: 0.0123 AC: 3065 AN: 250196 Hom.: 228 AF XY: 0.00936 AC XY: 1268 AN XY: 135402

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.00703

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000550

Gnomad OTH exome AF: 0.00719

GnomAD4 exome AF: 0.00519 AC: 7583 AN: 1461562 Hom.: 560 Cov.: 33 AF XY: 0.00457 AC XY: 3322 AN XY: 727048

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.00848

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.000391

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.0465 AC: 7091 AN: 152336 Hom.: 585 Cov.: 33 AF XY: 0.0451 AC XY: 3361 AN XY: 74498

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000764

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0309 Hom.: 178

Bravo AF: 0.0540

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CDK9-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2019

This variant is classified as 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	-0.84
Cadd	Benign	1.1
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.022
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: rs3217744; hg19: chr9-130550487;