9-127787511-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001261.4(CDK9):c.175-7C>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 0.00327 in 1,606,150 control chromosomes in the GnomAD database, including 197 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 0.0043 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (167 hom.)
• Consequence: CDK9 NM_001261.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003190
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0250

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-127787511-C-T is Benign according to our data. Variant chr9-127787511-C-T is described in ClinVar as [Benign]. Clinvar id is 780135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK9	NM_001261.4	c.175-7C>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.175-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001261.4	P1
CDK9	ENST00000421939.5	c.526-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		3
CDK9	ENST00000491521.1	n.12C>T		non_coding_transcript_exon_variant	1/4	3
CDK9	ENST00000480353.5	n.250-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 649 AN: 152182 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0952

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00959

GnomAD3 exomes AF: 0.00857 AC: 2154 AN: 251430 Hom.: 106 AF XY: 0.00798 AC XY: 1085 AN XY: 135884

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.102

Gnomad SAS exome AF: 0.00297

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.000668

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00317 AC: 4603 AN: 1453850 Hom.: 167 Cov.: 29 AF XY: 0.00305 AC XY: 2210 AN XY: 723840

Gnomad4 AFR exome AF: 0.000690

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.0774

Gnomad4 SAS exome AF: 0.00319

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.000503

Gnomad4 OTH exome AF: 0.00925

GnomAD4 genome AF: 0.00426 AC: 649 AN: 152300 Hom.: 30 Cov.: 32 AF XY: 0.00466 AC XY: 347 AN XY: 74472

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.0951

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00123 Hom.: 8

Bravo AF: 0.00454

Asia WGS AF: 0.0480 AC: 165 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

CDK9-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 20, 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	-0.82
Cadd	Benign	4.1
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
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: rs3217739; hg19: chr9-130549790;