rs142347393

Positions:

• chr17-39530840-C-A
• chr17-39530840-C-T

Variant summary

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

The NM_016507.4(CDK12):​c.3997C>A​(p.Arg1333Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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)
• Consequence: CDK12 NM_016507.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.19

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08647308).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK12	NM_016507.4	c.3997C>A	p.Arg1333Ser	missense_variant	14/14	ENST00000447079.6	NP_057591.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK12	ENST00000447079.6	c.3997C>A	p.Arg1333Ser	missense_variant	14/14	1	NM_016507.4	ENSP00000398880	P4
CDK12	ENST00000430627.6	c.3970C>A	p.Arg1324Ser	missense_variant	14/14	1		ENSP00000407720	A1
CDK12	ENST00000584336.1	n.959C>A		non_coding_transcript_exon_variant	1/1
CDK12	ENST00000559663.2	c.3760+4524C>A		intron_variant, NMD_transcript_variant		5		ENSP00000453329

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.049	.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.044
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.19	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.83	N;N
REVEL	Benign	0.071
Sift	Benign	0.045	D;T
Sift4G	Benign	0.40	T;T
Polyphen		0.0020	B;B
Vest4		0.13
MutPred		0.11		.;Gain of phosphorylation at R1333 (P = 0.0103);
MVP		0.36
MPC		0.21
ClinPred		0.51	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.14

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: chr17-37687093;