chr17-39462684-G-C

Position:

• chr17-39462684-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016507.4(CDK12):​c.613G>C​(p.Glu205Gln) 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: 3.82

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22025448).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK12	NM_016507.4	c.613G>C	p.Glu205Gln	missense_variant	1/14	ENST00000447079.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK12	ENST00000447079.6	c.613G>C	p.Glu205Gln	missense_variant	1/14	1	NM_016507.4	P4
CDK12	ENST00000430627.6	c.613G>C	p.Glu205Gln	missense_variant	1/14	1		A1
CDK12	ENST00000584632.5	c.613G>C	p.Glu205Gln	missense_variant	1/13	5
CDK12	ENST00000559663.2	c.613G>C	p.Glu205Gln	missense_variant, NMD_transcript_variant	1/21	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Mar 06, 2023

The c.613G>C (p.E205Q) alteration is located in exon 1 (coding exon 1) of the CDK12 gene. This alteration results from a G to C substitution at nucleotide position 613, causing the glutamic acid (E) at amino acid position 205 to be replaced by a glutamine (Q). 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	Uncertain	0.46
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0091	T;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.69	.;N;N
MutationTaster	Benign	0.88	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.75	.;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0040	.;D;D
Sift4G	Benign	0.26	T;T;T
Polyphen		1.0, 0.99	.;D;D
Vest4		0.095, 0.10
MutPred		0.26		Loss of ubiquitination at K208 (P = 0.212);Loss of ubiquitination at K208 (P = 0.212);Loss of ubiquitination at K208 (P = 0.212);
MVP		0.37
MPC		0.33
ClinPred		0.59	D
GERP RS		5.1
Varity_R		0.25
gMVP		0.041

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-37618937;