rs587778177

Variant names:

• chr17-39526125-C-A
• NM_016507.4:c.3569C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-39526125-C-A
• chr17-39526125-C-G

Variant summary

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

The NM_016507.4(CDK12):​c.3569C>A​(p.Pro1190His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDK12 NM_016507.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.51

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=0.35166427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK12	NM_016507.4	c.3569C>A	p.Pro1190His	missense_variant	Exon 13 of 14	ENST00000447079.6	NP_057591.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK12	ENST00000447079.6	c.3569C>A	p.Pro1190His	missense_variant	Exon 13 of 14	1	NM_016507.4	ENSP00000398880.4
CDK12	ENST00000430627.6	c.3569C>A	p.Pro1190His	missense_variant	Exon 13 of 14	1		ENSP00000407720.2
CDK12	ENST00000584632.5	c.3566C>A	p.Pro1189His	missense_variant	Exon 13 of 13	5		ENSP00000464641.1
CDK12	ENST00000559663.2	n.3569C>A		non_coding_transcript_exon_variant	Exon 13 of 21	5		ENSP00000453329.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.8	.;L;L
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.4	.;D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.99, 0.99	.;D;D
Vest4		0.47, 0.45
MutPred		0.28		.;Gain of catalytic residue at I1188 (P = 0.1099);Gain of catalytic residue at I1188 (P = 0.1099);
MVP		0.51
MPC		0.76
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.26
gMVP		0.38

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: chr17-37682378;