5-69276573-C-G

Position:

• chr5-69276573-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001799.4(CDK7):​c.895C>G​(p.Pro299Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDK7 NM_001799.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

Genes affected

CDK7 (HGNC:1778): (cyclin dependent kinase 7) 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 Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression. This protein forms a trimeric complex with cyclin H and MAT1, which functions as a Cdk-activating kinase (CAK). It is an essential component of the transcription factor TFIIH, that is involved in transcription initiation and DNA repair. This protein is thought to serve as a direct link between the regulation of transcription and the cell cycle. [provided by RefSeq, Jul 2008]

CCDC125 (HGNC:28924): (coiled-coil domain containing 125) Enables identical protein binding activity. Involved in activation of GTPase activity; negative regulation of Rho protein signal transduction; and negative regulation of cell motility. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK7	NM_001799.4	c.895C>G	p.Pro299Ala	missense_variant	11/12	ENST00000256443.8	NP_001790.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK7	ENST00000256443.8	c.895C>G	p.Pro299Ala	missense_variant	11/12	1	NM_001799.4	ENSP00000256443.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461086 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726856

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2024

The c.895C>G (p.P299A) alteration is located in exon 11 (coding exon 11) of the CDK7 gene. This alteration results from a C to G substitution at nucleotide position 895, causing the proline (P) at amino acid position 299 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	0.0091	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.5	D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.62
MutPred		0.32		Loss of glycosylation at P299 (P = 0.022);.;.;
MVP		0.88
MPC		1.5
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs1219644441; hg19: chr5-68572400;