17-39462802-A-C

Position:

• chr17-39462802-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016507.4(CDK12):​c.731A>C​(p.Gln244Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK12 NM_016507.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.27

Genes affected

CDK12 (HGNC:24224): (cyclin dependent kinase 12) Enables RNA polymerase II CTD heptapeptide repeat kinase activity and cyclin binding activity. Involved in phosphorylation of RNA polymerase II C-terminal domain; protein autophosphorylation; and regulation of MAP kinase activity. Located in nuclear speck. Part of cyclin K-CDK12 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2944435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK12	NM_016507.4	c.731A>C	p.Gln244Pro	missense_variant	1/14	ENST00000447079.6	NP_057591.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK12	ENST00000447079.6	c.731A>C	p.Gln244Pro	missense_variant	1/14	1	NM_016507.4	ENSP00000398880	P4
CDK12	ENST00000430627.6	c.731A>C	p.Gln244Pro	missense_variant	1/14	1		ENSP00000407720	A1
CDK12	ENST00000584632.5	c.731A>C	p.Gln244Pro	missense_variant	1/13	5		ENSP00000464641
CDK12	ENST00000559663.2	c.731A>C	p.Gln244Pro	missense_variant, NMD_transcript_variant	1/21	5		ENSP00000453329

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jun 10, 2024

The c.731A>C (p.Q244P) alteration is located in exon 1 (coding exon 1) of the CDK12 gene. This alteration results from a A to C substitution at nucleotide position 731, causing the glutamine (Q) at amino acid position 244 to be replaced by a proline (P). 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	Benign	0.077
BayesDel_addAF	Benign	-0.0044	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0053	T;.;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	.;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	.;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0020	.;D;D
Sift4G	Benign	0.18	T;T;T
Polyphen		1.0, 0.97	.;D;D
Vest4		0.37, 0.45
MutPred		0.17		Loss of stability (P = 0.0358);Loss of stability (P = 0.0358);Loss of stability (P = 0.0358);
MVP		0.39
MPC		0.40
ClinPred		0.84	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.15

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: rs2049044466; hg19: chr17-37619055;