17-39462615-G-A

Variant summary

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

The NM_016507.4(CDK12):c.544G>A(p.Glu182Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDK12 NM_016507.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.19

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=0.26407513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK12	NM_016507.4	c.544G>A	p.Glu182Lys	missense_variant	1/14	ENST00000447079.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK12	ENST00000447079.6	c.544G>A	p.Glu182Lys	missense_variant	1/14	1	NM_016507.4	P4
CDK12	ENST00000430627.6	c.544G>A	p.Glu182Lys	missense_variant	1/14	1		A1
CDK12	ENST00000584632.5	c.544G>A	p.Glu182Lys	missense_variant	1/13	5
CDK12	ENST00000559663.2	c.544G>A	p.Glu182Lys	missense_variant, NMD_transcript_variant	1/21	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251346 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Apr 07, 2022

The c.544G>A (p.E182K) alteration is located in exon 1 (coding exon 1) of the CDK12 gene. This alteration results from a G to A substitution at nucleotide position 544, causing the glutamic acid (E) at amino acid position 182 to be replaced by a lysine (K). 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	0.78
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.0055	T;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.99, 0.98	.;D;D
Vest4		0.40, 0.44
MutPred		0.28		Gain of methylation at E182 (P = 0.0256);Gain of methylation at E182 (P = 0.0256);Gain of methylation at E182 (P = 0.0256);
MVP		0.31
MPC		0.37
ClinPred		0.68	D
GERP RS		5.2
Varity_R		0.28
gMVP		0.017

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: rs1289047193; hg19: chr17-37618868; COSMIC: COSV71000315;